RARE DISEASE
Extranodal nasal NK/T cell lymphoma
Extranodal nasal NK/T cell lymphoma
Extranodal nasal NK/T cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Synonyms: Angiocentric T-cell lymphoma, Lethal midline granuloma, NK/T-cell lymphoma, NKTCL, Nasal T/natural killer-cell lymphoma
Drug discovery
4
drugs
With orphan designations
Overview
Extranodal nasal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus-associated non-Hodgkin lymphoma, primarily involving the nasal cavity and upper aerodigestive tract. Characterized by necrotic midline lesions, it shows geographic predominance in Asia and Latin America. Diagnosis relies on histopathology, EBV in situ hybridization, and cytotoxic markers (e.g., CD56+, granzyme B). Resistance to CHOP chemotherapy necessitates tailored approaches, combining radiotherapy and asparaginase-based regimens for optimal outcomes [1][6][10].
Therapies
Early-stage: Concurrent/sequential chemoradiotherapy (e.g., DeVIC + 50 Gy RT) with 5-year survival >80% [8][13][14].
Advanced-stage: Asparaginase-based regimens (SMILE, DDGP) ± PD-1 inhibitors (pembrolizumab); 2-year survival ~40% [3][8][18].
Avoid anthracyclines; RT remains critical even for chemotherapy-responsive disease [5][13][19].
Categories: rare hematological diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,250 drug discovery papers about Extranodal nasal NK/T cell lymphoma, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,250 drug discovery papers about Extranodal nasal NK/T cell lymphoma, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-28 | Radiation dose de-escalation in early-stage extranodal natural killer/T-cell lymphoma treated with contemporary concurrent chemoradiotherapy in the intensity-modulated radiotherapy era.
This study aimed to evaluate whether radiation dose escalation improves survival outcomes in early-stage extranodal natural killer/T-cell lymphoma (ENKTL) treated with intensity-modulated radiotherapy (IMRT)-based concurrent chemoradiotherapy (CCRT). We retrospectively reviewed 72 patients with Ann Arbor stage I-II ENKTL treated at our institution from 2011 to 2025 with IMRT-based CCRT followed by sequential chemotherapy with etoposide, ifosfamide, dexamethasone, and L-asparaginase. Patients were stratified at the cohort median radiation dose and inverse probability of treatment weighting (IPTW) was applied to address potential confounding by indication. The primary endpoint was overall survival (OS); secondary endpoints were local progression-free survival (LPFS), progression-free survival (PFS), and toxicity. Using the cohort median (54 Gy) as the cutoff, patients were divided into <54 Gy (n = 32) and ≥54 Gy (n = 40) groups. The ≥54 Gy group had more female patients (p = 0.007), with older age and higher prognostic index for natural killer lymphoma-Epstein-Barr virus (PINK-E) scores. IPTW was applied in 62 patients with available PINK-E data. No significant difference was observed between dose groups in OS (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.22 to 2.58), LPFS (HR, 1.87; 95% CI, 0.54 to 6.51), or PFS (HR, 0.53; 95% CI, 0.23 to 1.23). No grade ≥4 toxicities occurred, and grade ≥2 toxicities did not differ between groups. In early-stage ENKTL treated with IMRT-based CCRT, radiation dose escalation beyond 54 Gy did not improve survival or local disease control. These findings suggest that higher radiation doses may be unnecessary in the modern IMRT era.
2026-09-18 | Synergistic Anti-Tumor Effect of Chidamide and Linperlisib on Natural Killer/T-Cell Lymphoma by Inhibiting PI3K/AKT/mTOR Pathway.
Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma subtype with limited treatment options, especially for relapsed or refractory patients. Chidamide, a histone deacetylase inhibitor, and linperlisib, a phosphatidylinositol-3-kinase (PI3K) inhibitor, have shown promise in treating peripheral T-cell lymphoma, but their effects on NKTCL are less explored. In this study, the therapeutic efficacy and mechanisms of combining chidamide and linperlisib in the treatment of NKTCL were investigated. Three human NKTCL cell lines (NKYS, KHYG1, and YT) were used to assess the effects of chidamide and linperlisib on cell proliferation, apoptosis, and the cell cycle. RNA-seq and Western blot assays were employed to uncover the underlying mechanisms, and a YT xenograft mouse model was used for in vivo validation. Both chidamide and linperlisib exhibited dose- and time-dependent anti-tumor effects, and their combination enhanced efficacy, reduced cell viability, and increased apoptosis. This combination induced G2/M cell cycle arrest. Transcriptomic, Western blot, and immunohistochemical analysis revealed significant inhibition of the PI3K/AKT/mTOR pathway, which correlated with upregulation of the tumor suppressor PRDM1. These findings were confirmed in the YT xenograft model. In conclusion, the combination of chidamide and linperlisib has synergistic anti-tumor effects on NKTCL, which are mediated through inhibition of the PI3K/AKT/mTOR pathway, suggesting a promising therapeutic strategy for NKTCL management.
2026-09-15 | Oral manifestations and management of lymphoma-associated hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by dysregulated activation of cytotoxic T-lymphocytes and macrophages, with lymphoma-associated HLH (LA-HLH) carrying a particularly poor prognosis due to delayed diagnosis and lack of optimal treatment regimens. While the systemic features of LA-HLH-such as persistent fever, pancytopenia, and hepatosplenomegaly-are well-documented, its oral manifestations have not been previously described in the literature. We herein report a case of LA-HLH in a 28-year-old female patient who presented with intermittent fever along with recurrent oral ulcers. The patient had been diagnosed with ENKTL (non-nasal type, stage IVB, PINK-E 4, high risk) two years prior, with skin and muscle involvement, and had achieved remission after chemotherapy and autologous hematopoietic stem cell transplantation. A comprehensive diagnostic workup, including bone marrow biopsy and laboratory assessments, confirmed the diagnosis of LA-HLH secondary to relapsed extranodal NK/T-cell lymphoma (non-nasal type, stage IVB). The oral lesions were managed with Kangfuxin mouthwashes, while the underlying lymphoma and HLH were treated with dexamethasone and etoposide, combined with chidamide and tislelizumab. To the best of our knowledge, this is the first report documenting oral mucosal involvement by ENKTL occurring in a patient with LA-HLH. These oral lesions, as a manifestation of localized lymphoma progression, may serve as early clinical clues to lymphoma relapse with secondary HLH, rather than being a specific early sign of LA-HLH itself. Increased awareness of these potential oral findings among clinicians and dentists could facilitate earlier diagnosis of lymphoma relapse in LA-HLH patients and improve the multidisciplinary management of associated complications.
2026-08-30 | [Treatment landscape of mature NK/T-cell lymphomas: treatment outcomes in Japan and future prospects].
Mature NK/T-cell lymphomas are a rare group of lymphoma subtypes, represented by extranodal NK/T-cell lymphoma (ENKL) and aggressive NK-cell leukemia (ANKL). Both subtypes are strongly associated with Epstein-Barr virus and show a high prevalence, particularly in East Asia and Central and South America. In Japan, ENKL currently accounts for approximately 1% of all malignant lymphomas, whereas ANKL is even rarer, accounting for approximately 0.1%. ENKL and ANKL share many clinical and pathological features. However, as evidence regarding differences in molecular biological characteristics, including genetic and chromosomal abnormalities, has gradually accumulated, they have been recognized as distinct disease entities since the 2001 WHO classification (3rd edition). Since the 2000s, the treatment of ENKL has markedly advanced with the development of non-anthracycline-based regimens. In Japan, RT-2/3DeVIC for localized-stage ENKL and SMILE for stage IV and relapsed/refractory ENKL were developed and remain the current standard of care. In contrast, because ANKL is a rare disease and reports on its treatment are limited, it is usually treated using strategies for advanced-stage ENKL. This review focuses on ENKL and ANKL, providing an overview of their disease characteristics, evolving treatment and prognosis, and future challenges and perspectives.
2026-08-25 | Multimodal spatial profiling reveals distinct myeloid-defined ENKTL subgroups and tumor-myeloid cooperativity within prognostic inflammatory niche.
Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus (EBV)-associated malignancy with a heterogeneous tumor microenvironment, yet macrophage heterogeneity and tumor-macrophage crosstalk remain poorly defined. Here, we integrate spatial transcriptomic and proteomic profiling with single-cell spatial molecular imaging of ENKTL samples and identify two subgroups defined by distinct macrophage programs. Subgroup 1 is enriched for inflammatory macrophages exhibiting IFN-α/γ responses and immune-regulatory molecules including IDO1 and CD274, whereas Subgroup 2 is immune-quiescent and macrophage-sparse, with its macrophage compartment skewed towards STAB1 macrophages with scavenging features. Notably, an NF-κB-activated and EBV-associated tumor subset is specifically enriched in Subgroup 1, displaying concurrent immunostimulatory and immunoregulatory features that parallel the co-enriched myeloid states and showing reproducible sample-level associations with these myeloid states across datasets. Spatial neighborhood analysis further delineates an inflammation niche where NF-κB tumor cells physically co-localize with these inflammatory macrophages, accompanied by enhanced tumor-myeloid and myeloid-myeloid signaling, implicating a process of tumor-associated myeloid recruitment followed by CCL- and IL1-mediated myeloid self-reinforcement. Critically, higher abundance of this niche correlates with improved survival across independent cohorts, revealing contrasting spatial tumor-immune architectures with prognostic relevance. Together, our study provides a spatially resolved framework for understanding ENKTL biology and guiding immunotherapeutic strategies.
proteins
2026-06-26 | From ALL to Myeloid and NK Malignancies: Operationalizing "ASNS-Low" for L-Asparaginase Repurposing and Combination Therapy.
L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7-associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
2026-01-09 | Epstein-Barr Virus-Associated T/NK-Cell Neoplasms.
Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell neoplasms encompass a heterogeneous spectrum, ranging from persistent lymphoproliferative disorders (e.g., severe mosquito bite allergy, systemic chronic active EBV disease) to highly aggressive malignancies (e.g., extranodal NK/T-cell lymphoma [ENKTL], aggressive NK-cell leukemia). Genomic and epigenetic studies have revealed shared host genetic alterations-most notably in JAK-STAT signaling, epigenetic regulators, TP53, and DDX3X-supporting a pathogenic and clinicobiological continuum across these disorders. Defective EBV further reshapes viral gene expression programs and contributes to oncogenesis. l-asparaginase-based chemoradiotherapy has improved outcomes in early-stage ENKTL; however, effective treatments for advanced-stage disease and other EBV-associated T/NK-cell neoplasms remain limited. Emerging molecular subclassifications and large-scale prospective cohorts can help clarify disease heterogeneity and accelerate the development of precision therapeutic strategies.
2026-01-01 | Extranodal NK/T‐Cell Lymphoma, Nasal Type of Head and Neck in a Pediatric Population: A Systematic Review
Objective This review aims to identify and evaluate the management options for the extranodal NK/T‐cell lymphoma, nasal type of head and neck in the pediatric population. Methods The study was conducted based on a comprehensive literature review from 2009 to 2025. The following keywords were used: extranodal NK/T cell lymphoma and children and head and neck. Results The clinical data, including sex, age, symptoms, localization at presentation, correlation with EBV infection, treatment, and its outcome, were analyzed. A total of 64 patients were evaluated. Among these cases, the nasal site was the most involved region. Positive results for EBV infection were present in 100% of patients. The mortality rate in this study was 25%. Conclusions This systematic review highlights a clear male predominance, a pronounced geographic concentration of cases in East Asia, and underscores the diagnostic importance of EBV positivity in the diagnosis of ENKTL. In the case of the chronic course of destructive processes in aerodigestive organs with no improvement after standard treatment, NK‐cell lymphomas should be considered in the differential diagnosis. Multimodal treatment strategies, particularly asparaginase‐based chemotherapy with or without radiotherapy, are associated with improved outcomes, although disease‐related mortality remains substantial. Given the limited number of pediatric cases and the heterogeneity of available data, further prospective, multicenter studies with standardized diagnostic and therapeutic approaches are essential to optimize management and improve long‐term survival.
2026-01-01 | The Cryptic Invader: Midfacial Destruction in Extranodal NK/T-Cell Lymphoma – Case report with Narrative Review
Introduction: Extranodal natural killer/T-cell lymphoma, nasal type, is a rare and aggressive malignancy of the midline facial structures, strongly associated with Epstein-Barr virus-driven oncogenesis.Because it may mimic infectious, inflammatory, granulomatous, or necrotizing disorders, diagnosis is often delayed until progressive angiocentric tissue destruction becomes clinically evident.Case report: We report the case of a 40-year-old woman whose initially subtle nasal obstruction and discharge progressed to severe midfacial destruction, with a friable mass eroding the septum and palate.Histopathological examination showed pandermal, subcutaneous, and angioinvasive atypical lymphoid infiltrates.Immunohistochemistry and Epstein-Barr virus-encoded RNA in situ hybridization confirmed Epstein-Barr virus-associated cytotoxic T/natural killer-cell lineage, establishing the diagnosis.The patient was started on an L-asparaginase--based regimen, in line with current therapeutic approaches that favor non-anthracycline protocols.Conclusions: This case highlights diagnostic challenges of extranodal natural killer/T-cell lymphoma, nasal type, its ability to mimic granulomatous and necrotizing conditions, and the essential role of early biopsy with comprehensive immunophenotyping.The case is presented together with a review of the biology, diagnostic pathway, and evolving therapeutic landscape of this aggressive neoplasm.
cell therapies
2026-07-20 | Upfront Autologous Stem Cell Transplantation in First Complete Remission for Advanced-Stage Extra-Nodal NK/T-Cell Lymphoma: A Multicenter Retrospective Study.
The aim of this study was to evaluate the effect of upfront autologous stem cell transplantation (ASCT) on the prognosis in patients with advanced-stage extra-nodal NK/T-cell lymphoma (NKTCL) achieving first complete remission (CR1) after frontline therapy. To this end, we retrospectively reviewed data from patients diagnosed with stage III or IV NKTCL who achieved CR1 after frontline treatment between 2006 and 2023 at 14 medical centers in China. A total of 107 patients were included in this study. The majority of patients (87%) received non-anthracycline-based first-line chemotherapy, and 38 (36%) received upfront ASCT consolidation at the time of CR1. With a median follow-up time of 39.8 months, progression-free survival (PFS) and overall survival (OS) rates were significantly better in the ASCT group than in the non-ASCT group (3-year PFS: 78.2% vs. 54.6%, p = 0.005; 3-year OS: 86.0% vs. 68.9%, p = 0.04). However, in the subgroup of patients receiving non-anthracycline-based chemotherapy (N = 93), ASCT was significantly associated with better PFS (3-year PFS: 77.6% vs. 59.3%, p = 0.025) but not with OS (3-year OS: 85.6% vs. 74.8%, p = 0.164). In multivariate analyzes, upfront ASCT was an independent predictor of better PFS (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.15-0.88, p = 0.025) but not OS after adjusting for baseline prognostic index of NK-cell lymphoma (PINK), types of first-line chemotherapy, and local radiotherapy. After propensity score matched analyzes, upfront ASCT remained significantly associated with better PFS but not with OS. These real-world data suggest upfront ASCT prolongs PFS in patients with advanced-stage NKTCL in CR1, yet its impact on OS remains unclear.
2026-07-11 | HSCT May Improve Survival in Advanced Extranodal NK/T-Cell Lymphoma: A Single-Center Retrospective Study.
Extranodal NK/T-cell lymphoma (ENKTCL) is a rare and aggressive lymphoid malignancy highly associated with Epstein-Barr virus (EBV) infection. Patients with stage III or higher disease often have a poor prognosis. This study retrospectively reviewed the treatment courses of 34 patients with relapsed/refractory (R/R) ENKTCL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center between January 2019 and July 2024. The results showed that in this study, the use of PD-1 inhibitors before transplantation, the number of treatment lines, and whether the plasma EBV was negative or not had no significant impact on OS and PFS. Patients achieving complete response (CR) or partial response (PR) prior to allo-HSCT exhibited a more favorable prognosis. Conversely, a history of chronic active EBV infection (CAEBV) before transplantation and EBV reactivation post-transplantation were associated with inferior survival, suggesting poor prognostic outcomes. Genetic susceptibility analysis revealed that patients with advanced ENKTCL frequently harbored hemophagocytic lymphohistiocytosis (HLH)-associated gene variants. LYST gene variants were the most commonly identified HLH-related alterations, and patients developing HLH experienced significantly higher non-relapse mortality (NRM). Furthermore, TP53 gene variants were associated with post-allo-HSCT relapse. In conclusion, Allogeneic HSCT may improve survival in selected high-risk, advanced-stage R/R ENKTCL patients. These single-center, retrospective findings are hypothesis-generating and require validation in larger, multi-center studies with longer follow-up.
2026-07-01 | Case Report: refractory hemophagocytic lymphohistiocytosis progression despite complete metabolic response in a patient with stage IV extranodal NK/T-cell lymphoma: clinical observation of “tumor-immune dissociation” phenomenon
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-associated mature T- and NK-cell neoplasm with a notably high prevalence in Asian populations. It is a leading malignant cause of secondary hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune hyperactivation syndrome associated with poor prognosis in ENKTCL patients. Current clinical guidelines lack evidence-based post-remission monitoring protocols for the early detection of HLH progression in ENKTCL patients who achieve complete metabolic response (CMR). We report the case of a 59-year-old woman with stage IVB extra-nasal ENKTCL and biopsy-confirmed secondary HLH at initial diagnosis, who achieved radiologic CMR following frontline HLH induction therapy and three cycles of lymphoma-specific chemotherapy. Despite persistent CMR, she developed refractory HLH progression, and ultimately died from progressive HLH and multiple organ failure. Serial dynamic monitoring of tumor biomarkers (plasma EBV-DNA), direct immune activation biomarkers (soluble CD25 [sCD25]), and HLH-specific disease activity biomarkers (serum ferritin, triglycerides) revealed a “tumor-immune dissociation” phenomenon—aberrant immune activation and HLH progression occurring independently of radiologic tumor progression, with sCD25 remaining persistently elevated throughout the disease course, though subclinical EBV reactivation or microscopic disease undetectable by PET/CT cannot be excluded. This case demonstrates that HLH can progress independently of radiologically detectable tumor burden even after achieving CMR, underscoring a critical limitation of current response-adapted follow-up strategies. The observed “tumor-immune dissociation” highlights the urgent need to incorporate immune activation biomarkers into routine surveillance for high-risk ENKTCL patients, as well as to conduct early evaluations of allogeneic hematopoietic stem cell transplantation for eligible individuals.
2026-06-18 | NK cell-based immunotherapy.
NK cells have rapidly become a leading platform for cancer immunotherapy. Unlike T cells, NK cells recognize transformed cells through integrated signals from inhibitory and activating receptors, enabling allogeneic "off-the-shelf" therapies without risk of graft-versus-host disease and low rates of cytokine release syndrome and neurotoxicity. Refinement in sourcing of allogenic NK cells, especially umbilical cord blood and induced pluripotent stem cells, ex vivo activation and expansion, CAR engineering, and combinations with novel engagers have resulted in clinically applicable products with encouraging activity and excellent safety. However, barriers remain, including limited in vivo persistence, host rejection of allogeneic cells, and inefficient trafficking into solid tumors. Venues of progress include multiantigen and logic-gated CAR platforms, inducible safety switches, cytokine armoring, and metabolic and transcriptional rewiring to improve NK fitness. As NK cell therapies progress into the clinic, exploration of rational combinations with checkpoint inhibitors, small-molecule kinase inhibitors, chemotherapy, and radiotherapy warrant study.
2026-04-01 | Efficacy of modified dendritic cell-cytokine-induced killer cells loaded with tumour stem cell membrane microparticle therapy in the treatment of relapsed or refractory T- and NK-cell lymphoid proliferations and lymphomas: a report of three cases.
The prognosis of relapsed or refractory T-cell and NK-cell lymphoid proliferations and lymphomas (R/R T/NK-LPD/LYM) remains poor. Modified dendritic cell–cytokine-induced killer (DC–CIK) cells loaded with tumour stem cell (TSC) membrane microparticles (MMPs) can improve the targeted killing activity against tumours. However, the use of this treatment has not been reported for R/R T/NK-LPD/LYM. Herein, we report 3 cases. Case 1 involved an 8-year-old male who presented with bilateral cervical painless lymphadenopathy and a left elbow mass. Case 2 involved a 44-year-old man with recurrent nasal congestion and a runny nose. Case 3 involved a 49-year-old man whose bilateral cervical, axillary, and inguinal lymph nodes were enlarged. The biopsy results revealed T-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS); extranodal NK/T-cell lymphoma, nasal type; and nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type (nTFHL-AI) for Patients 1, 2, and 3, respectively. All three patients ultimately underwent modified dendritic cell–cytokine-induced killer cell therapy loaded with tumour stem cell membrane microparticles following disease progression, relapse, and chemotherapy-associated complications after first-line therapy and multiple lines of salvage therapy. Following treatment with modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles, two of these three patients achieved complete and durable remission, whereas the third patient achieved a partial response, with no treatment-related adverse events reported. At the most recent follow-up, two patients maintained stable disease (SD) with preserved quality of life, while one patient experienced progressive disease (PD) and died because of multiple organ dysfunction syndrome secondary to transplantation-associated colitis. To our knowledge, this is the first report of the use of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles for the treatment of R/R T/NK-LPD/LYM. Our findings warrant further evaluation of this novel targeted immunotherapy in future prospective clinical trials.
antibodies
2026-09-04 | Primary central nervous system extranodal NK/T-cell lymphoma predominantly composed of anaplastic cells: A case report.
Extranodal NK/T-cell lymphoma (ENKTL) of the central nervous system (CNS) is very rare. We herein report a case of ENKTL originating from the CNS in a 79-year-old woman. The patient presented with episodic seizures, left-sided limb weakness, altered mental status, and dysarthria for more than 1 month. Radiological examination revealed a solitary mass in the (laterality) frontal lobe of the brain, which was surgically removed. Histopathology revealed a tumor showing diffuse growth of large anaplastic cells with multiple reniform nuclei, horseshoe nuclei, and doughnut-like nuclei. Immunohistochemically, the tumor cells were diffusely positive for CD3, CD30, Gramazyme B, and TIA1 and negative for ALK and CD56. It was almost misdiagnosed as ALK-negative anaplastic large cell lymphoma, but positivity for cytotoxic markers and EBER-ISH helped establish the diagnosis of ENKTL. To the best of our knowledge, this anaplastic variant of ENKTL has not been reported in the CNS. We present this case to describe an uncommon aggressive variant of ENKTL at CNS as a rare location with diagnostic pitfalls.
2026-08-28 | Single-cell profiling of natural killer/T-cell lymphoma reveals stratified immune features and potential therapeutic implications.
Tumor cell heterogeneity and interactions with the immune microenvironment play a key role in the progression and therapeutic efficacy of natural killer/T-cell lymphoma (NKTCL). We perform single-cell RNA sequencing analysis of 63 samples, integrating spatial transcriptomics, bulk transcriptomics, proteomics, and metabolomics to dissect inter- and intra-tumoral heterogeneity. Four meta-programs (MP) are identified, including MP1 (immune-responsive), MP2 (proliferative), MP3 (inflammatory), and MP4 (metabolic), each linked to distinct molecular and immune features. MP1 exhibits an immune-exhausted tumor microenvironment and high programmed death-ligand 1 expression, suggesting a potential response to immune checkpoint blockade. MP2 shows an immune-desert phenotype with elevated HDAC2 and MKI67 expression, indicating epigenetic regulation in tumor proliferation. MP3 is characterized by a myeloid-dominant tumor microenvironment, JAK/STAT pathway activation, and an aggressive clinical course. MP4 exhibits a distinct amino acid metabolic profile and enriched tertiary lymphoid structures. Collectively, our study provides a high-resolution molecular atlas of NKTCL heterogeneity, offering insights into patient stratification and potential avenues for future therapeutic development.
2026-08-12 | ZBED6-driven nucleotide metabolic reprogramming improves sensitivity to anti-PD1 therapy in NK/T cell lymphoma.
NK/T-cell lymphoma (NKTL) is a highly aggressive non-Hodgkin's lymphoma characterized by extranodal involvement. Programmed cell death protein 1 (PD-1) monoclonal antibody (anti-PD1) treatment is ineffective in some patients, leading to recurrence or metastasis. The resistance to anti-PD1 treatment remains a major challenge in clinics. To identify the core molecules responsible for anti-PD1 treatment resistance and explore the possible molecular mechanisms behind it, simulating the human immune microenvironment during PD-1 treatment is essential. In this study, human peripheral blood mononuclear cells (PBMCs) were transplanted into immunodeficient mice to reconstitute human immunity in mice. The results showed that after immune reconstitution, human immune cells, especially T cells, remain at a high level (≥90%) for at least 4 weeks, indicating that human PBMCs were successfully reconstituted in immunodeficient mice. Two weeks after PBMCs implantation, human NKTL cells (SNK1, KHYG1 and YT) were subcutaneously inoculated into the right lower abdomen of mice. Then, high-dose anti-PD1 treatment was initiated (about 50 mm3, Sintilimab, twice a week, 10 mg/kg each time). The tumor from the mice was removed (≤than 1500 mm3) to prepare a single-cell suspension and re-implanted into the mice. The above process was repeated 5 times (280 days in total). The tumor growth inhibition (TGI) values of NKTL cells before and after induction (71.89% and 1.08% for KHYG1 cells, 54.37% and 3.79% for SNK1 cells, 51.17% and 6.34% for YT cells, respectively) confirmed the successful construction of anti-hPD1-induced resistance NKTL cells (SNK1-Re, KHYG1-Re and YT-Re). Subsequently, we performed transcriptomic, proteomic, and metabolomic analyses on the above resistant and sensitive cell lines. Through multiple functional experiments and clinical sample verification, we confirmed that the transcriptional repressor Zinc finger BED-type containing 6 (ZBED6) was a key biomarker for anti-PD1 treatment resistance in NKTL. Downregulated ZBED6 creates a thymidine-deficient environment by E2F transcription factor 1 (E2F1)-ribonucleoside-diphosphate reductase subunit M2 (RRM2)/dihydropyrimidine dehydrogenase (DPYD), in which drug-resistant tumor cells scavenge thymidine (TdR) from the tumor microenvironment via solute carrier family 29 member 1 (SLC29A1) to increase nucleotide synthesis, thereby establishing an immunosuppressive niche, resulting in the ineffectiveness of anti-PD1 immunotherapy.
2026-08-09 | Real-world outcomes of T cell lymphoma in a tertiary cancer center in Saudi Arabia.
T-cell and natural-killer (T/NK)-cell lymphomas are rare and aggressive malignancies. Prior to our study, no dedicated institutional survival analyses of T/NK-cell lymphomas had been published from Saudi Arabia. To evaluate the clinical characteristics, prognostic factors, and survival outcomes of patients with T/NK-cell lymphoma treated at a tertiary cancer referral centre in Saudi Arabia. Retrospective cohort study. King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia; January 2016 to December 2022. We reviewed medical records of 89 adults with histologically confirmed T/NK-cell lymphomas, including precursor and mature subtypes. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors were assessed with univariate and multivariable Cox proportional hazards regression. To maintain a robust events-per-variable ratio, the multivariable model was restricted to four predictors. Five-year overall survival and identification of variables associated with mortality. 89 patients. The mean age was 49.5±20.5 years, and 62 patients (70%) were male. The most common subtypes were ALK-negative anaplastic large-cell lymphoma (n=20, 22%) and peripheral T-cell lymphoma, not otherwise specified (n=15, 17%). For the entire cohort (N=89), the 5-year OS was 56% (95% CI, 44%-67%); the Kaplan-Meier estimated mean OS over the full available follow-up was 116.4 months. In multivariable analysis restricted to 70 patients with complete data (26 deaths), elevated lactate dehydrogenase (LDH) (hazard ratio [HR]=7.66; 95% confidence interval [CI], 1.77-33.19; P=.006), Eastern Cooperative Oncology Group (ECOG) performance status >2 (HR=4.26; 95% CI, 1.60-11.33; P=.004), and renal insufficiency (HR=3.06; 95% CI, 1.34-6.97; P=.008) were independent predictors of worse survival. Anemia trended toward worse survival but did not reach independent significance (HR=2.30; 95% CI, 0.95-5.58; P=.066). Elevated LDH, poor performance status, and renal insufficiency are strong independent predictors of inferior survival. Stem cell transplantation did not demonstrate a survival benefit in this cohort. These findings underscore the importance of baseline laboratory and clinical variables for risk stratification and provide groundwork for multicentre studies and therapeutic optimisation in Saudi Arabia. Sample size and single-centre retrospective design limit generalisability. Transplant-specific details in treatment regimens were not evaluated.
2026-08-05 | Extranodal NK/T-cell lymphoma, nasal type, presenting as a necrotic palatal ulcer.
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive Epstein-Barr virus (EBV)-associated lymphoma that predominantly involves the nasal cavity and upper aerodigestive tract. Primary oral manifestations are rare and may clinically mimic benign inflammatory or infectious conditions, resulting in delayed diagnosis. This report presents a rare case of ENKTL initially manifesting as a rapidly progressive necrotizing palatal ulcer. A 44-year-old man presented with a three-week history of a necrotic ulcer on the posterior hard palate. Imaging revealed extensive midfacial destruction, including palatal perforation, nasal septal erosion, turbinate destruction, ethmoidal involvement, and medial orbital wall extension. Histopathologic examination demonstrated atypical large lymphoid cells with extensive necrosis and infiltration into adipose and muscle tissue. Immunohistochemical staining demonstrated diffuse expression of LCA and CD3, focal expression of CD30, absence of CD20, ALK, and CD56 expression, and a high proliferative activity, as evidenced by a Ki-67 index of approximately 90%. Based on the histomorphologic and immunophenotypic features, extranodal NK/T-cell lymphoma was suspected. Chromogenic in situ hybridization (CISH) for Epstein-Barr virus-encoded RNA (EBER) demonstrated strong nuclear positivity in atypical lymphoid cells, confirming the diagnosis of ENKTL, nasal type. The patient achieved complete remission after chemotherapy; however, eight months later, the patient developed a systemic relapse that was diagnosed as peripheral T-cell lymphoma. This case highlights the diagnostic complexity of ENKTL presenting as a destructive palatal lesion. Comprehensive histopathologic evaluation, detailed immunophenotyping, and EBV confirmation by EBER are essential for accurate diagnosis and timely oncologic management. ENKTL should be considered in the differential diagnosis of rapidly progressive oral necrotic lesions unresponsive to conventional therapy.
other
2026-08-10 | Pediatric Extranodal NK/T-Cell Lymphoma Involving the Nasal Cavity: A Clinicopathological Case Report
Introduction: Extranodal NK/T-cell lymphoma, nasal type, is a rare and aggressive form of non-Hodgkin lymphoma strongly linked to Epstein–Barr virus. Pediatric cases are extremely uncommon and often difficult to diagnose due to nonspecific symptoms and a broad differential diagnosis. ENKTL typically involves the nasal cavity and upper aerodigestive tract, leading to progressive nasal obstruction, ulceration, and necrosis, with potential extension into adjacent facial structures. Case report: The article presents a rare case of ENKTL in a 15-year-old girl with a four-year history of nasal obstruction and crusting, ultimately progressing to a necrotic nasal cavity mass with septal perforation. The patient was treated with a DDGP regimen (dexamethasone, PEG-asparaginase, gemcitabine, cisplatin) and completed five cycles. Sequential X-ray photon radiotherapy (6 MV) was administered to a cumulative dose of 50 Gy. Follow-up demonstrated complete tumor remission. Conclusions: This case underscores the diagnostic complexity of extranodal NK/T-cell lymphoma, nasal type, in pediatric patients, especially when clinical manifestations resemble chronic inflammatory or autoimmune disorders. Persistent nonspecific nasal symptoms, septal perforation, and extensive mucosal necrosis should prompt consideration of an underlying malignancy and necessitate histopathological confirmation.
2025-10-30 | Smo gene silencing: a promising strategy for natural killer/t-cell lymphoma treatment via modulating proliferation and apoptosis.
Natural killer/T-cell lymphoma (NKTCL) is a malignancy with a poor prognosis. The Smoothened (Smo) protein is implicated in NKTCL growth. This study employed lentiviral vector-mediated Smo RNA interference (LV-Smo-RNAi) to silence the Smo gene in the human NKTCL cell line SNT8. Fluorescence microscopy, qRT-PCR, and Western blot verified the reduction of Smo mRNA and protein levels. The CCK-8 assay showed that Smo silencing inhibited cell proliferation. Flow cytometry with annexin V-PE/7-AAD double staining indicated an increased apoptosis rate. Moreover, the expression of GLI family zinc finger 1 (Gli1) and programmed death-ligand 1 (PD-L1) was downregulated. In vivo, xenotransplantation experiments demonstrated that Smo silencing led to slower tumor growth with reduced tumor volume and weight. Overall, Smo gene silencing holds great potential as a novel molecular-targeted therapy approach for NKTCL by effectively suppressing cell proliferation and promoting apoptosis.
2025-09-13 | A Systematic Review of MicroRNAs in Nasal NK/T-Cell Lymphoma: Diagnostic, Prognostic, and Therapeutic Perspectives.
Nasal NK/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with significant predominance with Epstein-Barr virus infection. MicroRNAs (miRNAs) have been found to be key regulators in cancer biology that influence tumorigenesis, disease progression, and immune evasion. This systematic review examines the role of miRNAs in diagnostics, prognosis, and treatment of NKTCL. PubMed and SCOPUS databases were systematically searched using the keywords "miRNAs" and "nasal lymphoma." Duplicate removal and selection based on the inclusion criteria produced 15 studies for final inclusion. Study design, specific miRNAs under study, and their relevance to NKTCL have been extracted for this narrative synthesis. PRISMA guidelines were followed, and results were narratively synthesized. In the selected studies, miRNAs showed their utility as potential diagnostic markers. Downregulated miRNAs, including miR-15a, miR-101, and miR-342-3p, differentiated NKTCL from normal tissue, while EBV-encoded miRNAs, including miR-BART20-5p and miR-BART8, were identified as potential circulating biomarkers. Prognostically, miRNAs such as miR-223 and miR-342-3p were associated with poor survival and aggressive disease features. Therapeutically, miRNA-based interventions targeting EBV miRNAs, such as miR-BART20-5p and miR-BART9, were emphasized for their ability to modulate immune pathways and oncogenic signaling. Despite these promising reports, heterogeneity in study designs and geographic settings limits their generalization. miRNAs are emerging as key players in the treatment of NKTCL, with application in diagnosis, prognosis, and therapy. Larger, heterogeneous cohorts and the progression of miRNA-based therapeutic research should further validate such studies. This review highlights the potential of miRNA in translation into better outcomes in NKTCL patients.
2025-04-10 | Dynamic change in Epstein-Barr virus DNA predicts prognosis in early stage natural killer/T-cell lymphoma with pegaspargase-based treatment: long-term follow-up and biomarker analysis from the NHL-004 multicenter randomized study.
The multi-center randomized phase III NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus the methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer / T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. A total of 256 eligible patients aged 14-70 years were randomly assigned (1:1) to the ESA or the MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in the ESA and MESA arms (hazard ratio [HR]=0.78 [95% CI: 0.46-1.33], P=0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR=0.74 [95% CI: 0.40-1.37], P=0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease / progressive disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with up-regulated chromatin remodeling alterations, immune escape-related genes, and decreased infiltrating monocytes / M1 macrophages. With low toxicity, non-intravenous administration, and an outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided a clinical rationale for future mechanism-based therapy in NKTCL.
2023-10-06 | Innovative Strategies of Reprogramming Immune System Cells by Targeting CRISPR/Cas9-Based Genome-Editing Tools: A New Era of Cancer Management.
The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.
small molecules
2026-09-28 | Radiation dose de-escalation in early-stage extranodal natural killer/T-cell lymphoma treated with contemporary concurrent chemoradiotherapy in the intensity-modulated radiotherapy era.
This study aimed to evaluate whether radiation dose escalation improves survival outcomes in early-stage extranodal natural killer/T-cell lymphoma (ENKTL) treated with intensity-modulated radiotherapy (IMRT)-based concurrent chemoradiotherapy (CCRT). We retrospectively reviewed 72 patients with Ann Arbor stage I-II ENKTL treated at our institution from 2011 to 2025 with IMRT-based CCRT followed by sequential chemotherapy with etoposide, ifosfamide, dexamethasone, and L-asparaginase. Patients were stratified at the cohort median radiation dose and inverse probability of treatment weighting (IPTW) was applied to address potential confounding by indication. The primary endpoint was overall survival (OS); secondary endpoints were local progression-free survival (LPFS), progression-free survival (PFS), and toxicity. Using the cohort median (54 Gy) as the cutoff, patients were divided into <54 Gy (n = 32) and ≥54 Gy (n = 40) groups. The ≥54 Gy group had more female patients (p = 0.007), with older age and higher prognostic index for natural killer lymphoma-Epstein-Barr virus (PINK-E) scores. IPTW was applied in 62 patients with available PINK-E data. No significant difference was observed between dose groups in OS (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.22 to 2.58), LPFS (HR, 1.87; 95% CI, 0.54 to 6.51), or PFS (HR, 0.53; 95% CI, 0.23 to 1.23). No grade ≥4 toxicities occurred, and grade ≥2 toxicities did not differ between groups. In early-stage ENKTL treated with IMRT-based CCRT, radiation dose escalation beyond 54 Gy did not improve survival or local disease control. These findings suggest that higher radiation doses may be unnecessary in the modern IMRT era.
2026-09-18 | Synergistic Anti-Tumor Effect of Chidamide and Linperlisib on Natural Killer/T-Cell Lymphoma by Inhibiting PI3K/AKT/mTOR Pathway.
Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma subtype with limited treatment options, especially for relapsed or refractory patients. Chidamide, a histone deacetylase inhibitor, and linperlisib, a phosphatidylinositol-3-kinase (PI3K) inhibitor, have shown promise in treating peripheral T-cell lymphoma, but their effects on NKTCL are less explored. In this study, the therapeutic efficacy and mechanisms of combining chidamide and linperlisib in the treatment of NKTCL were investigated. Three human NKTCL cell lines (NKYS, KHYG1, and YT) were used to assess the effects of chidamide and linperlisib on cell proliferation, apoptosis, and the cell cycle. RNA-seq and Western blot assays were employed to uncover the underlying mechanisms, and a YT xenograft mouse model was used for in vivo validation. Both chidamide and linperlisib exhibited dose- and time-dependent anti-tumor effects, and their combination enhanced efficacy, reduced cell viability, and increased apoptosis. This combination induced G2/M cell cycle arrest. Transcriptomic, Western blot, and immunohistochemical analysis revealed significant inhibition of the PI3K/AKT/mTOR pathway, which correlated with upregulation of the tumor suppressor PRDM1. These findings were confirmed in the YT xenograft model. In conclusion, the combination of chidamide and linperlisib has synergistic anti-tumor effects on NKTCL, which are mediated through inhibition of the PI3K/AKT/mTOR pathway, suggesting a promising therapeutic strategy for NKTCL management.
2026-09-15 | Oral manifestations and management of lymphoma-associated hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by dysregulated activation of cytotoxic T-lymphocytes and macrophages, with lymphoma-associated HLH (LA-HLH) carrying a particularly poor prognosis due to delayed diagnosis and lack of optimal treatment regimens. While the systemic features of LA-HLH-such as persistent fever, pancytopenia, and hepatosplenomegaly-are well-documented, its oral manifestations have not been previously described in the literature. We herein report a case of LA-HLH in a 28-year-old female patient who presented with intermittent fever along with recurrent oral ulcers. The patient had been diagnosed with ENKTL (non-nasal type, stage IVB, PINK-E 4, high risk) two years prior, with skin and muscle involvement, and had achieved remission after chemotherapy and autologous hematopoietic stem cell transplantation. A comprehensive diagnostic workup, including bone marrow biopsy and laboratory assessments, confirmed the diagnosis of LA-HLH secondary to relapsed extranodal NK/T-cell lymphoma (non-nasal type, stage IVB). The oral lesions were managed with Kangfuxin mouthwashes, while the underlying lymphoma and HLH were treated with dexamethasone and etoposide, combined with chidamide and tislelizumab. To the best of our knowledge, this is the first report documenting oral mucosal involvement by ENKTL occurring in a patient with LA-HLH. These oral lesions, as a manifestation of localized lymphoma progression, may serve as early clinical clues to lymphoma relapse with secondary HLH, rather than being a specific early sign of LA-HLH itself. Increased awareness of these potential oral findings among clinicians and dentists could facilitate earlier diagnosis of lymphoma relapse in LA-HLH patients and improve the multidisciplinary management of associated complications.
2026-08-30 | [Treatment landscape of mature NK/T-cell lymphomas: treatment outcomes in Japan and future prospects].
Mature NK/T-cell lymphomas are a rare group of lymphoma subtypes, represented by extranodal NK/T-cell lymphoma (ENKL) and aggressive NK-cell leukemia (ANKL). Both subtypes are strongly associated with Epstein-Barr virus and show a high prevalence, particularly in East Asia and Central and South America. In Japan, ENKL currently accounts for approximately 1% of all malignant lymphomas, whereas ANKL is even rarer, accounting for approximately 0.1%. ENKL and ANKL share many clinical and pathological features. However, as evidence regarding differences in molecular biological characteristics, including genetic and chromosomal abnormalities, has gradually accumulated, they have been recognized as distinct disease entities since the 2001 WHO classification (3rd edition). Since the 2000s, the treatment of ENKL has markedly advanced with the development of non-anthracycline-based regimens. In Japan, RT-2/3DeVIC for localized-stage ENKL and SMILE for stage IV and relapsed/refractory ENKL were developed and remain the current standard of care. In contrast, because ANKL is a rare disease and reports on its treatment are limited, it is usually treated using strategies for advanced-stage ENKL. This review focuses on ENKL and ANKL, providing an overview of their disease characteristics, evolving treatment and prognosis, and future challenges and perspectives.
2026-08-25 | Multimodal spatial profiling reveals distinct myeloid-defined ENKTL subgroups and tumor-myeloid cooperativity within prognostic inflammatory niche.
Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive Epstein-Barr virus (EBV)-associated malignancy with a heterogeneous tumor microenvironment, yet macrophage heterogeneity and tumor-macrophage crosstalk remain poorly defined. Here, we integrate spatial transcriptomic and proteomic profiling with single-cell spatial molecular imaging of ENKTL samples and identify two subgroups defined by distinct macrophage programs. Subgroup 1 is enriched for inflammatory macrophages exhibiting IFN-α/γ responses and immune-regulatory molecules including IDO1 and CD274, whereas Subgroup 2 is immune-quiescent and macrophage-sparse, with its macrophage compartment skewed towards STAB1 macrophages with scavenging features. Notably, an NF-κB-activated and EBV-associated tumor subset is specifically enriched in Subgroup 1, displaying concurrent immunostimulatory and immunoregulatory features that parallel the co-enriched myeloid states and showing reproducible sample-level associations with these myeloid states across datasets. Spatial neighborhood analysis further delineates an inflammation niche where NF-κB tumor cells physically co-localize with these inflammatory macrophages, accompanied by enhanced tumor-myeloid and myeloid-myeloid signaling, implicating a process of tumor-associated myeloid recruitment followed by CCL- and IL1-mediated myeloid self-reinforcement. Critically, higher abundance of this niche correlates with improved survival across independent cohorts, revealing contrasting spatial tumor-immune architectures with prognostic relevance. Together, our study provides a spatially resolved framework for understanding ENKTL biology and guiding immunotherapeutic strategies.
proteins
2026-06-26 | From ALL to Myeloid and NK Malignancies: Operationalizing "ASNS-Low" for L-Asparaginase Repurposing and Combination Therapy.
L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7-associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies.
2026-01-30 | Hemophagocytic lymphohistiocytosis associated with extranodal NK/T cell lymphoma, nasal type or aggressive NK cell leukemia: a retrospective multicenter study of Jiangsu Cooperative Lymphoma Group (JCLG).
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, among which NK-cell malignancy-associated HLH represents a clinically rare entity that has not been systematically investigated. The multicenter retrospective cohort study analyzed data from 136 adult patients diagnosed with HLH related to NK-cell malignancies between 2010 and 2024. The results demonstrated that initial treatment with etoposide-containing HLH therapy improved 60-day survival rates (P = 0.009) but did not affect overall survival (OS) (P = 0.306), whereas asparaginase-containing lymphoma regimens significantly improved both OS (P = 0.025) and 60-day survival rates (P = 0.016) in treatment-naive patients. By multivariate analysis, significant independent predictors of 60-day poor outcomes included serum albumin level < 30 g/L (HR, 2.03; 95% CI, 1.08-3.83; P = 0.029), platelet count < 20 × 10⁹/L (HR, 2.70; 95% CI, 1.46-4.99; P = 0.002), and Epstein-Barr virus DNA (whole blood) > 33,850 copies/mL (HR, 1.97; 95% CI, 1.01-3.81; P = 0.045). ECOG performance status ≥ 2 (HR, 2.00; 95% CI, 1.24-3.23; P = 0.004) and platelet count < 20 × 10⁹/L (HR, 7.61; 95% CI, 2.14-27.09; P = 0.002) were independent risk factors for poor OS. Therefore, we recommend asparaginase-based regimens as first-line therapy for treatment-naive adult patients with HLH related to NK-cell malignancies. Future multicenter prospective studies are warranted to optimize asparaginase-containing regimens, evaluate novel combination strategies, and establish precision risk-prediction models to guide clinical practice.
2026-01-09 | Epstein-Barr Virus-Associated T/NK-Cell Neoplasms.
Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell neoplasms encompass a heterogeneous spectrum, ranging from persistent lymphoproliferative disorders (e.g., severe mosquito bite allergy, systemic chronic active EBV disease) to highly aggressive malignancies (e.g., extranodal NK/T-cell lymphoma [ENKTL], aggressive NK-cell leukemia). Genomic and epigenetic studies have revealed shared host genetic alterations-most notably in JAK-STAT signaling, epigenetic regulators, TP53, and DDX3X-supporting a pathogenic and clinicobiological continuum across these disorders. Defective EBV further reshapes viral gene expression programs and contributes to oncogenesis. l-asparaginase-based chemoradiotherapy has improved outcomes in early-stage ENKTL; however, effective treatments for advanced-stage disease and other EBV-associated T/NK-cell neoplasms remain limited. Emerging molecular subclassifications and large-scale prospective cohorts can help clarify disease heterogeneity and accelerate the development of precision therapeutic strategies.
2026-01-01 | Extranodal NK/T‐Cell Lymphoma, Nasal Type of Head and Neck in a Pediatric Population: A Systematic Review
Objective This review aims to identify and evaluate the management options for the extranodal NK/T‐cell lymphoma, nasal type of head and neck in the pediatric population. Methods The study was conducted based on a comprehensive literature review from 2009 to 2025. The following keywords were used: extranodal NK/T cell lymphoma and children and head and neck. Results The clinical data, including sex, age, symptoms, localization at presentation, correlation with EBV infection, treatment, and its outcome, were analyzed. A total of 64 patients were evaluated. Among these cases, the nasal site was the most involved region. Positive results for EBV infection were present in 100% of patients. The mortality rate in this study was 25%. Conclusions This systematic review highlights a clear male predominance, a pronounced geographic concentration of cases in East Asia, and underscores the diagnostic importance of EBV positivity in the diagnosis of ENKTL. In the case of the chronic course of destructive processes in aerodigestive organs with no improvement after standard treatment, NK‐cell lymphomas should be considered in the differential diagnosis. Multimodal treatment strategies, particularly asparaginase‐based chemotherapy with or without radiotherapy, are associated with improved outcomes, although disease‐related mortality remains substantial. Given the limited number of pediatric cases and the heterogeneity of available data, further prospective, multicenter studies with standardized diagnostic and therapeutic approaches are essential to optimize management and improve long‐term survival.
2026-01-01 | The Cryptic Invader: Midfacial Destruction in Extranodal NK/T-Cell Lymphoma – Case report with Narrative Review
Introduction: Extranodal natural killer/T-cell lymphoma, nasal type, is a rare and aggressive malignancy of the midline facial structures, strongly associated with Epstein-Barr virus-driven oncogenesis.Because it may mimic infectious, inflammatory, granulomatous, or necrotizing disorders, diagnosis is often delayed until progressive angiocentric tissue destruction becomes clinically evident.Case report: We report the case of a 40-year-old woman whose initially subtle nasal obstruction and discharge progressed to severe midfacial destruction, with a friable mass eroding the septum and palate.Histopathological examination showed pandermal, subcutaneous, and angioinvasive atypical lymphoid infiltrates.Immunohistochemistry and Epstein-Barr virus-encoded RNA in situ hybridization confirmed Epstein-Barr virus-associated cytotoxic T/natural killer-cell lineage, establishing the diagnosis.The patient was started on an L-asparaginase--based regimen, in line with current therapeutic approaches that favor non-anthracycline protocols.Conclusions: This case highlights diagnostic challenges of extranodal natural killer/T-cell lymphoma, nasal type, its ability to mimic granulomatous and necrotizing conditions, and the essential role of early biopsy with comprehensive immunophenotyping.The case is presented together with a review of the biology, diagnostic pathway, and evolving therapeutic landscape of this aggressive neoplasm.
cell therapies
2026-07-20 | Upfront Autologous Stem Cell Transplantation in First Complete Remission for Advanced-Stage Extra-Nodal NK/T-Cell Lymphoma: A Multicenter Retrospective Study.
The aim of this study was to evaluate the effect of upfront autologous stem cell transplantation (ASCT) on the prognosis in patients with advanced-stage extra-nodal NK/T-cell lymphoma (NKTCL) achieving first complete remission (CR1) after frontline therapy. To this end, we retrospectively reviewed data from patients diagnosed with stage III or IV NKTCL who achieved CR1 after frontline treatment between 2006 and 2023 at 14 medical centers in China. A total of 107 patients were included in this study. The majority of patients (87%) received non-anthracycline-based first-line chemotherapy, and 38 (36%) received upfront ASCT consolidation at the time of CR1. With a median follow-up time of 39.8 months, progression-free survival (PFS) and overall survival (OS) rates were significantly better in the ASCT group than in the non-ASCT group (3-year PFS: 78.2% vs. 54.6%, p = 0.005; 3-year OS: 86.0% vs. 68.9%, p = 0.04). However, in the subgroup of patients receiving non-anthracycline-based chemotherapy (N = 93), ASCT was significantly associated with better PFS (3-year PFS: 77.6% vs. 59.3%, p = 0.025) but not with OS (3-year OS: 85.6% vs. 74.8%, p = 0.164). In multivariate analyzes, upfront ASCT was an independent predictor of better PFS (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.15-0.88, p = 0.025) but not OS after adjusting for baseline prognostic index of NK-cell lymphoma (PINK), types of first-line chemotherapy, and local radiotherapy. After propensity score matched analyzes, upfront ASCT remained significantly associated with better PFS but not with OS. These real-world data suggest upfront ASCT prolongs PFS in patients with advanced-stage NKTCL in CR1, yet its impact on OS remains unclear.
2026-07-11 | HSCT May Improve Survival in Advanced Extranodal NK/T-Cell Lymphoma: A Single-Center Retrospective Study.
Extranodal NK/T-cell lymphoma (ENKTCL) is a rare and aggressive lymphoid malignancy highly associated with Epstein-Barr virus (EBV) infection. Patients with stage III or higher disease often have a poor prognosis. This study retrospectively reviewed the treatment courses of 34 patients with relapsed/refractory (R/R) ENKTCL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center between January 2019 and July 2024. The results showed that in this study, the use of PD-1 inhibitors before transplantation, the number of treatment lines, and whether the plasma EBV was negative or not had no significant impact on OS and PFS. Patients achieving complete response (CR) or partial response (PR) prior to allo-HSCT exhibited a more favorable prognosis. Conversely, a history of chronic active EBV infection (CAEBV) before transplantation and EBV reactivation post-transplantation were associated with inferior survival, suggesting poor prognostic outcomes. Genetic susceptibility analysis revealed that patients with advanced ENKTCL frequently harbored hemophagocytic lymphohistiocytosis (HLH)-associated gene variants. LYST gene variants were the most commonly identified HLH-related alterations, and patients developing HLH experienced significantly higher non-relapse mortality (NRM). Furthermore, TP53 gene variants were associated with post-allo-HSCT relapse. In conclusion, Allogeneic HSCT may improve survival in selected high-risk, advanced-stage R/R ENKTCL patients. These single-center, retrospective findings are hypothesis-generating and require validation in larger, multi-center studies with longer follow-up.
2026-07-01 | Case Report: refractory hemophagocytic lymphohistiocytosis progression despite complete metabolic response in a patient with stage IV extranodal NK/T-cell lymphoma: clinical observation of “tumor-immune dissociation” phenomenon
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-associated mature T- and NK-cell neoplasm with a notably high prevalence in Asian populations. It is a leading malignant cause of secondary hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune hyperactivation syndrome associated with poor prognosis in ENKTCL patients. Current clinical guidelines lack evidence-based post-remission monitoring protocols for the early detection of HLH progression in ENKTCL patients who achieve complete metabolic response (CMR). We report the case of a 59-year-old woman with stage IVB extra-nasal ENKTCL and biopsy-confirmed secondary HLH at initial diagnosis, who achieved radiologic CMR following frontline HLH induction therapy and three cycles of lymphoma-specific chemotherapy. Despite persistent CMR, she developed refractory HLH progression, and ultimately died from progressive HLH and multiple organ failure. Serial dynamic monitoring of tumor biomarkers (plasma EBV-DNA), direct immune activation biomarkers (soluble CD25 [sCD25]), and HLH-specific disease activity biomarkers (serum ferritin, triglycerides) revealed a “tumor-immune dissociation” phenomenon—aberrant immune activation and HLH progression occurring independently of radiologic tumor progression, with sCD25 remaining persistently elevated throughout the disease course, though subclinical EBV reactivation or microscopic disease undetectable by PET/CT cannot be excluded. This case demonstrates that HLH can progress independently of radiologically detectable tumor burden even after achieving CMR, underscoring a critical limitation of current response-adapted follow-up strategies. The observed “tumor-immune dissociation” highlights the urgent need to incorporate immune activation biomarkers into routine surveillance for high-risk ENKTCL patients, as well as to conduct early evaluations of allogeneic hematopoietic stem cell transplantation for eligible individuals.
2026-06-18 | NK cell-based immunotherapy.
NK cells have rapidly become a leading platform for cancer immunotherapy. Unlike T cells, NK cells recognize transformed cells through integrated signals from inhibitory and activating receptors, enabling allogeneic "off-the-shelf" therapies without risk of graft-versus-host disease and low rates of cytokine release syndrome and neurotoxicity. Refinement in sourcing of allogenic NK cells, especially umbilical cord blood and induced pluripotent stem cells, ex vivo activation and expansion, CAR engineering, and combinations with novel engagers have resulted in clinically applicable products with encouraging activity and excellent safety. However, barriers remain, including limited in vivo persistence, host rejection of allogeneic cells, and inefficient trafficking into solid tumors. Venues of progress include multiantigen and logic-gated CAR platforms, inducible safety switches, cytokine armoring, and metabolic and transcriptional rewiring to improve NK fitness. As NK cell therapies progress into the clinic, exploration of rational combinations with checkpoint inhibitors, small-molecule kinase inhibitors, chemotherapy, and radiotherapy warrant study.
2026-04-01 | Efficacy of modified dendritic cell-cytokine-induced killer cells loaded with tumour stem cell membrane microparticle therapy in the treatment of relapsed or refractory T- and NK-cell lymphoid proliferations and lymphomas: a report of three cases.
The prognosis of relapsed or refractory T-cell and NK-cell lymphoid proliferations and lymphomas (R/R T/NK-LPD/LYM) remains poor. Modified dendritic cell–cytokine-induced killer (DC–CIK) cells loaded with tumour stem cell (TSC) membrane microparticles (MMPs) can improve the targeted killing activity against tumours. However, the use of this treatment has not been reported for R/R T/NK-LPD/LYM. Herein, we report 3 cases. Case 1 involved an 8-year-old male who presented with bilateral cervical painless lymphadenopathy and a left elbow mass. Case 2 involved a 44-year-old man with recurrent nasal congestion and a runny nose. Case 3 involved a 49-year-old man whose bilateral cervical, axillary, and inguinal lymph nodes were enlarged. The biopsy results revealed T-lymphoblastic leukaemia/lymphoma, not otherwise specified (NOS); extranodal NK/T-cell lymphoma, nasal type; and nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type (nTFHL-AI) for Patients 1, 2, and 3, respectively. All three patients ultimately underwent modified dendritic cell–cytokine-induced killer cell therapy loaded with tumour stem cell membrane microparticles following disease progression, relapse, and chemotherapy-associated complications after first-line therapy and multiple lines of salvage therapy. Following treatment with modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles, two of these three patients achieved complete and durable remission, whereas the third patient achieved a partial response, with no treatment-related adverse events reported. At the most recent follow-up, two patients maintained stable disease (SD) with preserved quality of life, while one patient experienced progressive disease (PD) and died because of multiple organ dysfunction syndrome secondary to transplantation-associated colitis. To our knowledge, this is the first report of the use of modified dendritic cell–cytokine-induced killer cells loaded with tumour stem cell membrane microparticles for the treatment of R/R T/NK-LPD/LYM. Our findings warrant further evaluation of this novel targeted immunotherapy in future prospective clinical trials.
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2026-09-04 | Primary central nervous system extranodal NK/T-cell lymphoma predominantly composed of anaplastic cells: A case report.
Extranodal NK/T-cell lymphoma (ENKTL) of the central nervous system (CNS) is very rare. We herein report a case of ENKTL originating from the CNS in a 79-year-old woman. The patient presented with episodic seizures, left-sided limb weakness, altered mental status, and dysarthria for more than 1 month. Radiological examination revealed a solitary mass in the (laterality) frontal lobe of the brain, which was surgically removed. Histopathology revealed a tumor showing diffuse growth of large anaplastic cells with multiple reniform nuclei, horseshoe nuclei, and doughnut-like nuclei. Immunohistochemically, the tumor cells were diffusely positive for CD3, CD30, Gramazyme B, and TIA1 and negative for ALK and CD56. It was almost misdiagnosed as ALK-negative anaplastic large cell lymphoma, but positivity for cytotoxic markers and EBER-ISH helped establish the diagnosis of ENKTL. To the best of our knowledge, this anaplastic variant of ENKTL has not been reported in the CNS. We present this case to describe an uncommon aggressive variant of ENKTL at CNS as a rare location with diagnostic pitfalls.
2026-08-28 | Single-cell profiling of natural killer/T-cell lymphoma reveals stratified immune features and potential therapeutic implications.
Tumor cell heterogeneity and interactions with the immune microenvironment play a key role in the progression and therapeutic efficacy of natural killer/T-cell lymphoma (NKTCL). We perform single-cell RNA sequencing analysis of 63 samples, integrating spatial transcriptomics, bulk transcriptomics, proteomics, and metabolomics to dissect inter- and intra-tumoral heterogeneity. Four meta-programs (MP) are identified, including MP1 (immune-responsive), MP2 (proliferative), MP3 (inflammatory), and MP4 (metabolic), each linked to distinct molecular and immune features. MP1 exhibits an immune-exhausted tumor microenvironment and high programmed death-ligand 1 expression, suggesting a potential response to immune checkpoint blockade. MP2 shows an immune-desert phenotype with elevated HDAC2 and MKI67 expression, indicating epigenetic regulation in tumor proliferation. MP3 is characterized by a myeloid-dominant tumor microenvironment, JAK/STAT pathway activation, and an aggressive clinical course. MP4 exhibits a distinct amino acid metabolic profile and enriched tertiary lymphoid structures. Collectively, our study provides a high-resolution molecular atlas of NKTCL heterogeneity, offering insights into patient stratification and potential avenues for future therapeutic development.
2026-08-12 | ZBED6-driven nucleotide metabolic reprogramming improves sensitivity to anti-PD1 therapy in NK/T cell lymphoma.
NK/T-cell lymphoma (NKTL) is a highly aggressive non-Hodgkin's lymphoma characterized by extranodal involvement. Programmed cell death protein 1 (PD-1) monoclonal antibody (anti-PD1) treatment is ineffective in some patients, leading to recurrence or metastasis. The resistance to anti-PD1 treatment remains a major challenge in clinics. To identify the core molecules responsible for anti-PD1 treatment resistance and explore the possible molecular mechanisms behind it, simulating the human immune microenvironment during PD-1 treatment is essential. In this study, human peripheral blood mononuclear cells (PBMCs) were transplanted into immunodeficient mice to reconstitute human immunity in mice. The results showed that after immune reconstitution, human immune cells, especially T cells, remain at a high level (≥90%) for at least 4 weeks, indicating that human PBMCs were successfully reconstituted in immunodeficient mice. Two weeks after PBMCs implantation, human NKTL cells (SNK1, KHYG1 and YT) were subcutaneously inoculated into the right lower abdomen of mice. Then, high-dose anti-PD1 treatment was initiated (about 50 mm3, Sintilimab, twice a week, 10 mg/kg each time). The tumor from the mice was removed (≤than 1500 mm3) to prepare a single-cell suspension and re-implanted into the mice. The above process was repeated 5 times (280 days in total). The tumor growth inhibition (TGI) values of NKTL cells before and after induction (71.89% and 1.08% for KHYG1 cells, 54.37% and 3.79% for SNK1 cells, 51.17% and 6.34% for YT cells, respectively) confirmed the successful construction of anti-hPD1-induced resistance NKTL cells (SNK1-Re, KHYG1-Re and YT-Re). Subsequently, we performed transcriptomic, proteomic, and metabolomic analyses on the above resistant and sensitive cell lines. Through multiple functional experiments and clinical sample verification, we confirmed that the transcriptional repressor Zinc finger BED-type containing 6 (ZBED6) was a key biomarker for anti-PD1 treatment resistance in NKTL. Downregulated ZBED6 creates a thymidine-deficient environment by E2F transcription factor 1 (E2F1)-ribonucleoside-diphosphate reductase subunit M2 (RRM2)/dihydropyrimidine dehydrogenase (DPYD), in which drug-resistant tumor cells scavenge thymidine (TdR) from the tumor microenvironment via solute carrier family 29 member 1 (SLC29A1) to increase nucleotide synthesis, thereby establishing an immunosuppressive niche, resulting in the ineffectiveness of anti-PD1 immunotherapy.
2026-08-09 | Real-world outcomes of T cell lymphoma in a tertiary cancer center in Saudi Arabia.
T-cell and natural-killer (T/NK)-cell lymphomas are rare and aggressive malignancies. Prior to our study, no dedicated institutional survival analyses of T/NK-cell lymphomas had been published from Saudi Arabia. To evaluate the clinical characteristics, prognostic factors, and survival outcomes of patients with T/NK-cell lymphoma treated at a tertiary cancer referral centre in Saudi Arabia. Retrospective cohort study. King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia; January 2016 to December 2022. We reviewed medical records of 89 adults with histologically confirmed T/NK-cell lymphomas, including precursor and mature subtypes. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors were assessed with univariate and multivariable Cox proportional hazards regression. To maintain a robust events-per-variable ratio, the multivariable model was restricted to four predictors. Five-year overall survival and identification of variables associated with mortality. 89 patients. The mean age was 49.5±20.5 years, and 62 patients (70%) were male. The most common subtypes were ALK-negative anaplastic large-cell lymphoma (n=20, 22%) and peripheral T-cell lymphoma, not otherwise specified (n=15, 17%). For the entire cohort (N=89), the 5-year OS was 56% (95% CI, 44%-67%); the Kaplan-Meier estimated mean OS over the full available follow-up was 116.4 months. In multivariable analysis restricted to 70 patients with complete data (26 deaths), elevated lactate dehydrogenase (LDH) (hazard ratio [HR]=7.66; 95% confidence interval [CI], 1.77-33.19; P=.006), Eastern Cooperative Oncology Group (ECOG) performance status >2 (HR=4.26; 95% CI, 1.60-11.33; P=.004), and renal insufficiency (HR=3.06; 95% CI, 1.34-6.97; P=.008) were independent predictors of worse survival. Anemia trended toward worse survival but did not reach independent significance (HR=2.30; 95% CI, 0.95-5.58; P=.066). Elevated LDH, poor performance status, and renal insufficiency are strong independent predictors of inferior survival. Stem cell transplantation did not demonstrate a survival benefit in this cohort. These findings underscore the importance of baseline laboratory and clinical variables for risk stratification and provide groundwork for multicentre studies and therapeutic optimisation in Saudi Arabia. Sample size and single-centre retrospective design limit generalisability. Transplant-specific details in treatment regimens were not evaluated.
2026-08-05 | Extranodal NK/T-cell lymphoma, nasal type, presenting as a necrotic palatal ulcer.
Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive Epstein-Barr virus (EBV)-associated lymphoma that predominantly involves the nasal cavity and upper aerodigestive tract. Primary oral manifestations are rare and may clinically mimic benign inflammatory or infectious conditions, resulting in delayed diagnosis. This report presents a rare case of ENKTL initially manifesting as a rapidly progressive necrotizing palatal ulcer. A 44-year-old man presented with a three-week history of a necrotic ulcer on the posterior hard palate. Imaging revealed extensive midfacial destruction, including palatal perforation, nasal septal erosion, turbinate destruction, ethmoidal involvement, and medial orbital wall extension. Histopathologic examination demonstrated atypical large lymphoid cells with extensive necrosis and infiltration into adipose and muscle tissue. Immunohistochemical staining demonstrated diffuse expression of LCA and CD3, focal expression of CD30, absence of CD20, ALK, and CD56 expression, and a high proliferative activity, as evidenced by a Ki-67 index of approximately 90%. Based on the histomorphologic and immunophenotypic features, extranodal NK/T-cell lymphoma was suspected. Chromogenic in situ hybridization (CISH) for Epstein-Barr virus-encoded RNA (EBER) demonstrated strong nuclear positivity in atypical lymphoid cells, confirming the diagnosis of ENKTL, nasal type. The patient achieved complete remission after chemotherapy; however, eight months later, the patient developed a systemic relapse that was diagnosed as peripheral T-cell lymphoma. This case highlights the diagnostic complexity of ENKTL presenting as a destructive palatal lesion. Comprehensive histopathologic evaluation, detailed immunophenotyping, and EBV confirmation by EBER are essential for accurate diagnosis and timely oncologic management. ENKTL should be considered in the differential diagnosis of rapidly progressive oral necrotic lesions unresponsive to conventional therapy.
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2026-08-10 | Pediatric Extranodal NK/T-Cell Lymphoma Involving the Nasal Cavity: A Clinicopathological Case Report
Introduction: Extranodal NK/T-cell lymphoma, nasal type, is a rare and aggressive form of non-Hodgkin lymphoma strongly linked to Epstein–Barr virus. Pediatric cases are extremely uncommon and often difficult to diagnose due to nonspecific symptoms and a broad differential diagnosis. ENKTL typically involves the nasal cavity and upper aerodigestive tract, leading to progressive nasal obstruction, ulceration, and necrosis, with potential extension into adjacent facial structures. Case report: The article presents a rare case of ENKTL in a 15-year-old girl with a four-year history of nasal obstruction and crusting, ultimately progressing to a necrotic nasal cavity mass with septal perforation. The patient was treated with a DDGP regimen (dexamethasone, PEG-asparaginase, gemcitabine, cisplatin) and completed five cycles. Sequential X-ray photon radiotherapy (6 MV) was administered to a cumulative dose of 50 Gy. Follow-up demonstrated complete tumor remission. Conclusions: This case underscores the diagnostic complexity of extranodal NK/T-cell lymphoma, nasal type, in pediatric patients, especially when clinical manifestations resemble chronic inflammatory or autoimmune disorders. Persistent nonspecific nasal symptoms, septal perforation, and extensive mucosal necrosis should prompt consideration of an underlying malignancy and necessitate histopathological confirmation.
2025-10-30 | Smo gene silencing: a promising strategy for natural killer/t-cell lymphoma treatment via modulating proliferation and apoptosis.
Natural killer/T-cell lymphoma (NKTCL) is a malignancy with a poor prognosis. The Smoothened (Smo) protein is implicated in NKTCL growth. This study employed lentiviral vector-mediated Smo RNA interference (LV-Smo-RNAi) to silence the Smo gene in the human NKTCL cell line SNT8. Fluorescence microscopy, qRT-PCR, and Western blot verified the reduction of Smo mRNA and protein levels. The CCK-8 assay showed that Smo silencing inhibited cell proliferation. Flow cytometry with annexin V-PE/7-AAD double staining indicated an increased apoptosis rate. Moreover, the expression of GLI family zinc finger 1 (Gli1) and programmed death-ligand 1 (PD-L1) was downregulated. In vivo, xenotransplantation experiments demonstrated that Smo silencing led to slower tumor growth with reduced tumor volume and weight. Overall, Smo gene silencing holds great potential as a novel molecular-targeted therapy approach for NKTCL by effectively suppressing cell proliferation and promoting apoptosis.
2025-09-13 | A Systematic Review of MicroRNAs in Nasal NK/T-Cell Lymphoma: Diagnostic, Prognostic, and Therapeutic Perspectives.
Nasal NK/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with significant predominance with Epstein-Barr virus infection. MicroRNAs (miRNAs) have been found to be key regulators in cancer biology that influence tumorigenesis, disease progression, and immune evasion. This systematic review examines the role of miRNAs in diagnostics, prognosis, and treatment of NKTCL. PubMed and SCOPUS databases were systematically searched using the keywords "miRNAs" and "nasal lymphoma." Duplicate removal and selection based on the inclusion criteria produced 15 studies for final inclusion. Study design, specific miRNAs under study, and their relevance to NKTCL have been extracted for this narrative synthesis. PRISMA guidelines were followed, and results were narratively synthesized. In the selected studies, miRNAs showed their utility as potential diagnostic markers. Downregulated miRNAs, including miR-15a, miR-101, and miR-342-3p, differentiated NKTCL from normal tissue, while EBV-encoded miRNAs, including miR-BART20-5p and miR-BART8, were identified as potential circulating biomarkers. Prognostically, miRNAs such as miR-223 and miR-342-3p were associated with poor survival and aggressive disease features. Therapeutically, miRNA-based interventions targeting EBV miRNAs, such as miR-BART20-5p and miR-BART9, were emphasized for their ability to modulate immune pathways and oncogenic signaling. Despite these promising reports, heterogeneity in study designs and geographic settings limits their generalization. miRNAs are emerging as key players in the treatment of NKTCL, with application in diagnosis, prognosis, and therapy. Larger, heterogeneous cohorts and the progression of miRNA-based therapeutic research should further validate such studies. This review highlights the potential of miRNA in translation into better outcomes in NKTCL patients.
2025-04-10 | Dynamic change in Epstein-Barr virus DNA predicts prognosis in early stage natural killer/T-cell lymphoma with pegaspargase-based treatment: long-term follow-up and biomarker analysis from the NHL-004 multicenter randomized study.
The multi-center randomized phase III NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus the methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer / T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. A total of 256 eligible patients aged 14-70 years were randomly assigned (1:1) to the ESA or the MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in the ESA and MESA arms (hazard ratio [HR]=0.78 [95% CI: 0.46-1.33], P=0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR=0.74 [95% CI: 0.40-1.37], P=0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease / progressive disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with up-regulated chromatin remodeling alterations, immune escape-related genes, and decreased infiltrating monocytes / M1 macrophages. With low toxicity, non-intravenous administration, and an outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided a clinical rationale for future mechanism-based therapy in NKTCL.
2023-10-06 | Innovative Strategies of Reprogramming Immune System Cells by Targeting CRISPR/Cas9-Based Genome-Editing Tools: A New Era of Cancer Management.
The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.
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Drug Discovery Landscape
4 orphan drug designations for Extranodal nasal NK/T cell lymphoma.
4 orphan drug designations for Extranodal nasal NK/T cell lymphoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
EBV-induced natural T cell [EBViNT Cell] | cell therapies | FDA | Eutilex Co. Ltd | |
brentuximab vedotin | antibodies | FDA | Seattle Genetics, Inc. | |
Baltaleucel [CMD-003] | cell therapies | EMA | Scendea (NL) B.V. | |
Darinaparsin | small molecules | EMA | IDEA Innovative Drug European Associates (Ireland) Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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