small molecules

2026-09-25 | Custom bipolar electrode for bleomycin-based electrochemotherapy in patient-derived uveal melanoma in ovo and ex vivo.

Uveal melanoma (UM) is a rare tumor entity and the predominant primary intraocular malignancy in adulthood. Despite high local tumor control rates, metastatic disease remains frequent and systemic therapeutic options are limited. Electrochemotherapy (ECT) with bleomycin enhances intracellular drug uptake through electroporation (EP), thereby increasing targeted antitumor activity. This study investigated the effects of bleomycin-based ECT delivered using a custom bipolar electrode in UM patient-derived xenografts (PDX). UM PDX were analyzed in both in ovo and ex vivo experimental settings. Tumor grafts were treated with EP alone at voltage settings of 750 V or 1000 V, or with ECT combined with bleomycin at concentrations of 1 μg/mL or 2.5 μg/mL. Histological evaluation and immunofluorescence analyses were performed to assess tumor morphology, melanoma-associated marker expression, vascularization, proliferative activity and treatment-induced cell death pathways. ECT caused pronounced tumor disruption and decreased tumor size parameters compared with untreated controls, with statistically significant reductions in tumor area following EP at 750 V alone or combined with 2.5 μg/mL bleomycin and in tumor perimeter across all groups treated with EP at 750 V in ovo, while changes in the ex vivo model were not statistically significant. Expression of melanoma-associated markers, including a melanoma marker cocktail and Sox10, decreased following treatment, with significant differences observed in multiple in ovo and selected ex vivo conditions. Analysis of cell death markers indicated involvement of multiple cell death mechanisms, with statistically significant treatment-associated changes in markers of apoptosis, pyroptosis, necrosis and necroptosis detected in ovo, whereas gasdermin D expression did not reach statistical significance ex vivo. Treatment responses differed between experimental models and EP conditions, suggesting model-dependent cellular responses. Bleomycin-based ECT using a custom bipolar electrode induces substantial tumor damage in UM PDX in ovo and ex vivo. These findings support the potential application of bipolar electrode-based ECT for intraocular tumor treatment and provide a basis for further optimization of electrode design and translational investigation.

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2026-09-21 | Elesclomol-mediated cuproptosis overcomes cisplatin resistance by restricting epigenetically activated mitochondrial respiration: Novel therapeutic insights into cisplatin-elesclomol combination therapy.

Chemoresistance remains a significant challenge in cancer treatment, substantially limiting therapeutic efficacy. Cuproptosis is copper-induced cell death driven by mitochondrial protein aggregation and metabolic dysfunction. However, the involvement of cuproptosis in chemoresistance remains enigmatic. This study reveals that epigenetic remodeling augments mitochondrial respiration, thereby sensitizing cells to elesclomol-induced cuproptosis in cisplatin-resistant uveal melanoma (UM). First, we established cisplatin-resistant UM cell lines, which were validated in vitro and in vivo. A multi-omics analysis, including transcriptomics, metabolomics, and histone acetylation profiling (H3K9Ac/H3K27Ac CUT&Tag), revealed an upregulation of mitochondrial respiration and downregulation of glycolysis in cisplatin-resistant cells due to changes in histone acetylation. This metabolic reprogramming was associated with increased sensitivity to elesclomol-mediated cuproptosis, characterized by the diminishment of Fe-S cluster proteins and DLAT aggregation. Our research further delineated that the absence of FDX1 not only mitigated the sensitivity of chemoresistant UM cells to elesclomol but also attenuated copper-induced cell death, thereby substantiating the pivotal role of cuproptosis in this context. Therapeutically, employing zebrafish models, orthotopic xenografts, and patient-derived xenografts (PDXs), we confirmed the therapeutic efficacy of elesclomol in overcoming chemoresistance. Collectively, our study highlights a novel avenue for the development of a combinatorial therapeutic approach employing cisplatin and elesclomol to improve chemotherapy outcomes.

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2026-09-11 | Significance of adjuvant external beam radiotherapy of the orbit in managing uveal melanoma with extraocular extension.

Extraocular extension (EOE) is a known risk factor for metastasis in uveal melanoma. This long-term study investigates neoadjuvant and adjuvant external beam radiotherapy (EBRT) before and after enucleation of eyes with uveal melanoma and EOE with respect to survival, local tumour control, metastatic disease and side effects of radiotherapy. Retrospective, consecutive analysis of all patients with enucleation for uveal melanoma and histopathological evidence of EOE from June 1980 to April 2014. The entire cohort comprised 87 patients. 34 of those were lost to follow-up. Of the remaining 43 patients, 26 underwent adjuvant and/or neoadjuvant radiotherapy with a total orbital dose of 50-60 Gy, while the remaining 17 were treated with enucleation only. The mean follow-up time was 65.58±80.44 months (median 37 months) and 184.12±119.760 months (median 132 months) for those being alive at last follow-up. EBRT patients had significantly higher TNM (tumour, node, metastases) stages (p=0.033) and more extensive EOE (p=0.146). There was no significant difference in any relevant parameters between the two groups. The overall survival rate after 5 and 10 years was 32.6% and 16.2%, respectively. There was no evidence of a significantly later (p=0.573) or less frequent (p=0.999) occurrence of metastases in either group. There were no local recurrences in either group. Side effects of the radiotherapy occurred in 61.5%. Adjuvant or neoadjuvant EBRT had no survival benefit in uveal melanoma with EOE. No local recurrence was detected in either group.

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2026-09-04 | Fatty Acid-Binding Protein 5 Potentially Regulates the Proliferation and Metastasis of Uveal Melanoma Cells Through the PI3K/AKT/mTOR Signaling Pathway.

Uveal melanoma (UVM) is an aggressive intraocular tumor with limited effective treatments for metastatic disease. This study explored the pathways through which fatty acid-binding protein 5 (FABP5) promoted UVM progression. Single-cell RNA sequencing datasets were preprocessed by the Seurat package, and prognostic genes were screened using the survival package. A prognostic model was constructed via LASSO Cox regression, followed by Kaplan-Meier (KM) survival analysis. To characterize the tumor immune microenvironment, we evaluated immune cell infiltration using ssGSEA, ESTIMATE, and CIBERSORT algorithms, while GSEA was applied to identify enriched pathways. Additionally, immunotherapy response was predicted by TIDE, and tumor mutation burden (TMB) was calculated using Maftools. For in vivo validation, a nude mouse xenograft model was established, and Western blotting was performed on tumor tissues harvested from the xenograft assay. SPON2, MATK, and FABP5 were identified as hub genes in UVM and used to construct a prognostic model with a high AUC. Immune infiltration analysis revealed that high-risk patients exhibited features of immune evasion. Enrichment analysis further revealed that cytotoxic T-cell-related genes (MATK and FABP5) were enriched in the PI3K/AKT/mTOR pathway. FABP5 was overexpressed in UVM cells, whereas FABP5 silencing suppressed cell viability, proliferation, migration, and invasion, reduced MMP2 and MMP9 levels, promoted apoptosis, downregulated PI3K/AKT/mTOR pathway-related molecules, and upregulated apoptosis-related proteins. Notably, these effects could be reversed by the PI3K agonist 740Y-P. FABP5 promoted UVM cell proliferation and migration through the PI3K/AKT/mTOR pathway. Though the immune-infiltration analysis was hypothesis-generating, it may help identify patients likely to benefit from immunotherapy.

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2026-09-01 | Potential of Nanoparticle-Based Phototherapies for Future Treatment of Uveal Melanoma.

This review aims at exploring nanoparticle-based phototherapies of uveal melanoma (UM), the most common primary intraocular malignancy in adults with an estimated incidence of 5-7 cases per million individuals per year, a disproportionately high metastatic risk and poor prognosis in advanced stages. UM exhibits unique biological and anatomical features, including an immune-privileged ocular microenvironment, the blood-ocular barrier, and high melanin content, contributing to therapeutic complexity. Current treatments, including radiotherapy, surgery, and systemic therapies, achieve local tumor control but remain limited by adverse effects, recurrence, and insufficient efficacy against metastatic disease. Laser-based therapies, including transpupillary thermotherapy and photodynamic therapy, offer minimally invasive alternatives. However, their performance is constrained by limited light penetration, melanin-induced uneven absorption, and incomplete tumor eradication. Recent advances in nanotechnology offer opportunities to overcome these limitations. Nanoparticle-based phototherapies can improve tumor targeting, photosensitizer delivery, and localized activation while reducing off-target effects. Multifunctional nanoplatforms may combine imaging, drug delivery, and synergistic therapies such as immunotherapy or chemotherapy. Although promising preclinical results highlight improved tumor control and antitumor responses, challenges related to safety, biodistribution, and clinical translation remain. This review discusses these challenges and future directions for optimized nanoplatforms to improve disease management and metastasis prevention.

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cell therapies

2026-09-10 | Establishment of Stable Immortalized Human Choroidal Melanocytes for Ocular Research.

The short lifespan of primary normal choroidal melanocytes (NCMs) in vitro represents a major barrier to mechanistic, functional, and translational studies of choroid biology and uveal melanoma (UM). This study aimed to establish and characterize immortalized human NCM lines that retain melanocytic function, maintain a non-cancerous profile, and are amenable to gene editing. NCMs from four donors were immortalized by lentiviral transduction of cyclin-dependent kinase 4 (CDK4R24C), cyclin D1, and human telomerase reverse transcriptase (hTERT), establishing NCM-K4DT lines. Their morphology, melanocytic marker expression, proliferation, and functional properties (melanin synthesis and tyrosinase activity) were evaluated. Genomic stability was assessed by targeted mutation profiling, karyotyping, and copy number variation (CNV) analysis. The tumorigenicity was tested in immunodeficient mice. Plasmid-based CRISPR/Cas9 editing was performed to determine their suitability for gene editing. NCM-K4DT lines retained dendritic-shaped morphology, pigmentation, and expression of PMEL, TYRP1, Melan-A, and SOX10. Cells exhibited enhanced proliferative capacity with preserved cell cycle regulation. Melanin production and tyrosinase activity were comparable to primary NCMs. Genomic profiling confirmed the absence of UM-associated driver mutations and chromosomal abnormalities. In vivo growth assays demonstrated that NCM-K4DT lines did not form tumors within the 3-month observation period. Notably, NCM-K4DT cells were efficiently edited by CRISPR/Cas9. NCM-K4DT lines represent stable, non-cancerous, and genetically tractable models for studying choroidal melanocyte biology, modeling UM-associated mechanisms, and advancing therapeutic development in ocular research.

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2026-09-10 | Three-year outcomes of enucleation with cross-hatched rectus muscle attachment to a polyethylene orbital implant.

Orbital implant exposure remains a significant complication following enucleation. This study evaluates outcomes of enucleation using a polyethylene orbital implant with an integrated suturing platform and a modified cross-hatched rectus muscle attachment technique without oblique muscle reattachment. Retrospective series of 76 patients who underwent enucleation with a polyethylene orbital implant featuring an integrated suturing platform (October 2022-October 2025). Each of the four rectus muscles was sutured to the opposite suture point on the platform, creating a cross-hatched configuration over the anterior implant surface. Oblique muscles were transected and left. Primary outcomes included implant exposure, extrusion, infection, and socket complications; secondary outcomes included cosmetic appearance and prosthetic motility. The cohort comprised 76 patients (72 primary enucleations, 4 secondary implantations) with a mean follow-up of 28 months (range: 6-41). Indications included uveal melanoma (n = 52, 68%) and painful blind eye (n = 20, 26%); 4 patients (5%) underwent secondary implantation after prior trauma. Mean implant diameter was 20 mm (range: 14-22 mm). Complications comprised one suturing platform breakage and one implant exposure following orbital biopsy for suspected malignancy recurrence. No other complications occurred. Both primary and secondary groups achieved satisfactory cosmetic outcomes motility.    . Cross-hatched rectus muscle attachment to a polyethylene implant with a suturing platform, was associated with low complication rates and satisfactory outcomes. The cross-hatched configuration may provide adequate coverage despite absent oblique attachment, although coverage was not measured directly and no comparison group was available. Longer follow-up is needed to confirm risks.

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2026-09-07 | Key barriers in utilizing advanced T-cell engager strategies on solid tumors.

T cell engagers (TCEs) are engineered immune-mobilizing molecules that recruit T cells toward tumor cells. TCEs have demonstrated clinical efficacy in hematologic malignancies and currently show therapeutic potential in solid tumors through the approvals of tebentafusp and tarlatamab in uveal melanoma and small cell lung cancer. However, implementation of TCEs in solid tumors presents distinct challenges owing to tumor intrinsic features such as lack of specific antigens, biochemical and physical barriers that hinder T cell infiltration, complex immunosuppressive microenvironments, and intrinsic or acquired resistance to TCEs. This review aims to cover inclusive overview of the current portrait of TCEs for the treatment of solid tumors. It provides the mechanisms and design principle of TCE and addresses the challenges that impede treatment efficacy. Especially, we extensively depict the primary and acquired resistance mechanisms to TCEs. Moreover, we highlight the next-generation directions such as engineering of antibody format and combination strategies to overcome these challenges and improve the clinical efficacy. Integrating logical target selection, advanced engineering, biomarker-guided patient stratification, and deliberate clinical design allows TCEs to successfully expand the reach of novel immunotherapeutics into solid tumors.

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2026-07-01 | Three-dimensional platform-dependent modulation of stemness and EMT-associated gene expression in primary and metastatic uveal melanoma models.

Uveal melanoma is the most common primary intraocular malignancy in adults and is associated with high rates of metastatic progression. Although local tumour control is often achieved, effective therapies for metastatic disease remain limited. Three-dimensional culture systems more closely replicate aspects of the tumour microenvironment than conventional two-dimensional monolayers; however, differences between platforms and their impact on stemness- and epithelial-to-mesenchymal transition-associated transcription in uveal melanoma remain incompletely defined. Primary-derived and metastatic-derived uveal melanoma cell lines were cultured under four three-dimensional conditions, including AggreWell 800™, Biofloat™, Happy Cell Advanced Suspension Medium™, and hanging drop systems. Spheroid morphology and volume were quantified over ten days. Expression of cancer stem cell markers (CD133, CD24, CD44) and epithelial-to-mesenchymal transition-associated genes (E-cadherin, ZO-1, N-cadherin, Vimentin, Snail1, Snail2) was assessed relative to two-dimensional controls using quantitative polymerase chain reaction. All platforms supported spheroid formation, although growth dynamics differed between systems and site of tumour origin. Aggregation-based platforms produced more compact spheroids and greater volumetric expansion, particularly in metastatic-derived lines. Enhanced expression of CD133 and N-cadherin mRNA was observed in three-dimensional growth platforms, most prominently under structured aggregation conditions. Modulation of epithelial markers and transcription factors was variable and did not uniformly reflect complete epithelial-to-mesenchymal transition. Three-dimensional culture architecture was associated with differential modulation of stemness- and epithelial-to-mesenchymal transition-associated transcription in uveal melanoma. Platform selection and tumour origin were associated with differences in the phenotype observed in vitro and should be carefully aligned with specific biological endpoints when modelling disease progression.

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2026-06-09 | Exosome engineering: The promise and peril of targeted delivery for treating ocular diseases.

In the absence of acceptable cures for ocular diseases, stem cells and their paracrine agents, including exosomes, have become a promising therapeutic approaches. Exosomes are lipid spherical bilayer-encased particles and the smallest subtype of extracellular vehicles (EVs) that are secreted by cells to facilitate intercellular communication in the form of lipids, proteins, mRNAs, and small RNAs. Recent advances in exosome-based therapeutics have witnessed unique opportunities for treating ocular diseases, including autoimmune diseases, traumatic diseases, chorioretinal diseases, and uveal melanoma. Many studies demonstrated that exosomes, in particular, bioengineered exosomes have an impressive effect on target cells. The utilization of exosomes as delivery vectors to encapsulate both therapeutic genes and drugs, surface modification, and encapsulation by biomaterial could yield higher efficacy and avoid unnecessary immune responses. Several studies demonstrated the therapeutic effects of stem cells are due to engineered exosomes. However, exosome-based therapies also show some potential ocular risks. In this review, we first present the origins and general introduction to exosomes. We then provide an overview of the surface modification of MSC-derived exosomes, drug-loaded exosomes, bioengineering, and biomaterial-based exosomes. Eventually, we discussed available applications, their potential risks, and proposed future perspectives to address the translation and underlying issues related to ocular disease.

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antibodies

2026-09-25 | Survival of Patients With MBD4-Mutated Metastatic Uveal Melanoma Treated With Immune Checkpoint Inhibitors.

The prognosis of metastatic uveal melanoma (mUM) remains poor, and immune checkpoint inhibitors (ICIs) show limited efficacy, with response rates typically below 5%. Tebentafusp, an immune therapy targeting the gp100 protein, is the first drug to improve overall survival (OS) in mUM. Somatic MBD4 deficiency induces a hypermutated phenotype in a fraction of UM cases and may predict benefit from ICIs. We retrospectively analyzed patients with mUM carrying somatic or germline MBD4 alterations and treated with ICIs at Institut Curie (Paris, France). Clinical characteristics, treatments, and outcomes were collected. Twelve patients received ICIs (nine pembrolizumab, two ipilimumab + nivolumab, one pembrolizumab + lenvatinib). Most (83%) had M1a liver-only disease. The overall response rate was 50% (two complete, four partial) with a disease control rate of 83%. The median follow-up was 22 months (range, 9.9-116.8), and within this time frame median progression-free survival and OS were not reached. At 12 months, 73% of patients were progression free, and the estimated 2-year OS was 86%. We observed that, in patients with MBD4-mutated mUM, ICIs achieved a 50% response rate and prolonged survival, demonstrating strong and sustained clinical activity in this distinct molecular subgroup and exceeding outcomes reported with ICIs or tebentafusp. Our findings support further evaluation of MBD4 mutation as a predictive biomarker and suggest that ICIs should be considered as a preferred first-line option in MBD4-mutated mUM.

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2026-09-23 | ImmTACs overcome cytotoxic T cell suppression.

Synthetic T cell receptor (TCR) engagers are cancer therapeutics that activate T cells through recognition of antigens on the tumor cell surface. Immune-mobilizing monoclonal TCRs against cancer (ImmTAC) are composed of the extracellular domains of the alpha and beta chains of an affinity-enhanced TCR recognizing a tumor-associated antigenic peptide-major histocompatibility complex (MHC) complex linked to an scFv fragment of an antibody against CD3ε. A first-in-class ImmTAC, Tebentafusp, is approved for the treatment of metastatic uveal melanoma. Here we asked how ImmTACs activate human primary cytotoxic T lymphocytes (CTL) in response to antigen-presenting tumor target cells. We used a recently established experimental strategy to generate active and matched suppressed CTL in vitro. ImmTACs could elicit tumor cell cytolysis in response to endogenous antigen presentation by both active and suppressed CTL, but much less so for IFNγ secretion, in a manner dependent on the engager affinity for CD3ε. ImmTACs did so by enhancing the efficient execution of subcellular CTL polarization steps required for effective cytolysis and could trigger calcium signaling. These data establish that ImmTACs are powerful inducers of CTL cytotoxicity and do so with a comparable efficacy and mechanism as direct engagement of a TCR by peptide-MHC. ImmTACs retain this capability under suppressive conditions comparable to those in the tumor microenvironment.

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2026-09-01 | A review on toxicities of T-cell engager-based therapies in solid tumors.

T-cell engager (TCE)-based therapies represent an emerging and rapidly expanding class of immunotherapies in oncology. Initially developed for hematologic malignancies, TCEs are now entering the field of solid tumors. To date, two agents have received regulatory approval in this setting: Tebentafusp for metastatic uveal melanoma and Tarlatamab for small-cell lung cancer (SCLC). By physically linking a tumor-associated antigen (TAA) to a T-cell activating domain, most commonly cluster of differentiation (CD) 3, TCEs induce an immunological synapse that promotes targeted T-cell mediated cytotoxicity. This narrative review summarizes the most clinically relevant toxicities associated with TCEs in solid tumors, drawing on data from clinical trials and real-world experience. Tebentafusp exemplifies the safety profile of this therapeutic class, which is dominated by cytokine release syndrome (CRS) and cutaneous adverse events (AEs). These toxicities are typically early in onset, predictable, and reversible, occurring predominantly during the initial step-up dosing phase and decreasing substantially with subsequent administrations, consistent with immune adaptation. Tarlatamab, a Delta-like ligand 3 (DLL3) × CD3 bispecific TCE recently approved for SCLC, displays a toxicity profile similarly driven by immune activation, with CRS as the most frequent AE, generally of low grade and confined to early treatment cycles. In contrast, neurotoxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) occurs more frequently, though events are usually low grade, delayed relative to CRS. Other TCEs currently in clinical development target a wide range of TAAs and display a broadly similar toxicity profile, with CRS emerging as a class effect related to CD3-mediated T-cell activation. The incidence and severity of CRS are influenced by dosing strategies, with step-up dosing mitigating early toxicity. Cutaneous, immune-related, and hematologic AEs are generally infrequent and rarely severe. Continued optimization of antigen selection, molecular engineering, and pharmacokinetic parameters will be critical to improving the safety profile of TCEs gathering data from clinical trials and real-world experience.

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2026-08-25 | Real-world efficacy and toxicity of tebentafusp in metastatic uveal melanoma patients treated on the United Kingdom expanded access programme.

Metastatic uveal melanoma (mUM) carries a poor prognosis, with low response rates to checkpoint inhibitors. The phase III first-line IMCgp100-202 trial established tebentafusp, a bi-specific T cell engager, as the first treatment to demonstrate a survival benefit in mUM. Here, we report retrospective real-world efficacy and toxicity outcomes from the tebentafusp United Kingdom Expanded Access Programme (UK EAP). 115 HLA-A*02:01 positive patients with mUM were treated between July 2021 and June 2023. 10 of 18 UK EAP centres submitted data, and outcomes for 88 patients are reported here. Data was collected on demographics, disease characteristics, survival, and treatment toxicities and analyzed to identify factors impacting on median overall survival (mOS), median progression-free survival (mPFS), occurrence of cytokine release syndrome (CRS) and grade 3/4 rash. 71% of patients were treated in the first-line setting, with 94% having liver metastases. At a median follow-up of 12 months (range 0 to 34), mOS was 21 months (95% CI, 17 to NR), and mPFS was 2.76 months (95% CI, 2.53-3.22). The 12-month overall survival rate was 75% (95% CI, 66.11-85.6). Lower lactate dehydrogenase (LDH) and lower liver metastatic burden showed a trend towards improved overall survival, with baseline LDH ≥2× ULN conferring a very poor prognosis. Lower liver metastatic burden also associated with reduced frequency of CRS. No ≥ grade 3 toxicity was observed beyond dose 5. Tebentafusp on the UK EAP showed comparable real-world efficacy to the phase III first-line trial data, with manageable toxicities having implications for resource planning.

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2026-08-06 | Next-generation T cell engagers for cancer and autoimmune diseases.

T cell-engaging antibody constructs (TCEs) have emerged as a potent modality to treat cancer and autoimmune diseases. Twelve TCEs have been approved by the FDA and EMA for the treatment of hematological malignancies or solid tumors. Despite the varying designs and binding properties, they all lead to robust single-agent efficacy and approvals in refractory or relapsed leukemia, lymphomas, multiple myeloma (MM), small cell lung cancer, EpCAM-expressing cancers or uveal melanoma. Where comparisons can be deduced, TCEs appear to achieve response rates like those obtained with CAR-T cell therapies. Given the success of the first generation of TCEs, considerable attempts are underway to further improve upon this modality. With the goal of expanding TCEs into other malignant and autoimmune indications, and to further enhance efficacy and improve safety, a multitude of novel TCEs are currently in preclinical and clinical development. Here we review the current approaches to developing next-generation TCEs that can widen the therapeutic index, address heterogeneous target expression, and thereby potentially improve efficacy and safety.

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oligonucleotides

2026-09-21 | Single-cell transcriptomic atlas of the human fetal uveal tract reveals heterogeneity in melanocyte populations.

Uveal melanocytes are neural crest-derived cells contributing to ocular pigmentation, yet their developmental heterogeneity and microenvironmental roles remain poorly characterized. We present a single-cell transcriptomic atlas of the human fetal uveal tract, profiling 81,603 cells across 14 cell types from eight eyes at 12 and 20 post-conception weeks. Among 5,142 melanocytes, we identify four subpopulations, including a transcriptionally unique cluster enriched in posterior uveal tissue at later developmental stages. This population expresses NR2F1, FOXC1, and PITX2 alongside extracellular matrix and angiogenic genes and is predicted to communicate with Schwann cells, endothelial cells, and immune populations to modulate the uveal microenvironment. Multiplex immunofluorescence confirms MITF +/FOXC1 + co-expressing cells in fetal choroidal tissue, validating this population in situ. A refined gene signature from this cluster associates with high-metastatic risk across three independent uveal melanoma cohorts and is enriched in aggressive tumor cell states in single-cell data, implicating developmental program reactivation in disease progression.

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2026-08-05 | Identification and Validation of an E2F Targets-Related Gene Signature Risk Score Predicting the Prognosis of Patients with Uveal Melanoma.

Uveal melanoma (UM) is a challenging malignancy, in terms of diagnosis, risk stratification, and treatment associated with high morbidity and mortality rates. It has been demonstrated that E2F-related pathways play a significant role in the tumorigenesis and distant metastasis of UM. In this study, the E2F target-related genes were utilized to construct and validate a prognostic risk score for patients with UM. Using the TCGA-UVM cohort (n = 80), 192 E2F target genes were screened using gene set enrichment analysis (GSEA) to identify survival-associated genes. Prognostic genes were filtered using Kaplan-Meier analysis, univariate Cox regression, and LASSO, followed by multivariate Cox regression to construct a risk score model. The model was validated using the GSE22138 cohort (n = 63). Functional annotations of the risk score and its impact on stratifying tumor immune microenvironment components were assessed. A total of 9 genes (CDC25B, NME1, RFC2, PRDX4, NASP, UBE2S, PRKDC, MCM6, and LBR) passed the model construction pipeline. The risk score categorization system showed an independent prognostic power (HR: 2.34, 95% CI: 1.11-4.90, p = 0.025) and a good predictability of the survival outcome (receiver operating characteristic curve analysis: area under the curve = 0.730, 95% CI: 0.60-0.86, p = 0.002). When analyzing the most frequently mutated gene cohorts, the risk score was significantly lower in the mutated subgroups of GNAQ, SF3B1, and EIF1AX. In contrast, the risk score was notably higher in the BAP1 mutated subgroup. Copy number analysis of chromosomal arms showed significant correlations between the risk score and 1q, 3q, 3p, 6p, 8q. The high-risk group showed significant infiltration for NK cells, plasma B cells, gamma delta T cells, follicular T cells, M1 and M2 macrophages with lower infiltration of common myeloid progenitor cells. In addition, the high-risk group showed higher immune and microenvironment scores. The developed E2F target-related gene model offers a robust tool for predicting the prognosis of UM patients. As a potential risk stratification method for UM, this model could have clinical applications pending further evaluation.

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2026-05-20 | GSH-Responsive PBAE Polymers for IL-12 mRNA Delivery in Melanoma Immunotherapy.

Melanoma is a highly aggressive cancer with significant treatment challenges due to its immunosuppressive tumor microenvironment. Among its subtypes, uveal melanoma (UM), as a distinct subtype arising in the immune-privileged ocular site, currently lacks effective therapies to improve overall survival. We developed a glutathione (GSH)-responsive poly(β-amino ester) (PBAE) platform for intracellular IL-12 mRNA delivery. By optimizing the ratio of GSH-responsive diacrylate monomers and amine structures, we synthesized and screened a library of candidate polymers for transfection efficiency. Nanoparticle size, stability, GSH-triggered disassembly, and mRNA release were characterized. Cellular uptake, protein expression, endo/lysosomal escape, cytotoxicity, and systemic safety were assessed in vitro and in vivo. Efficacy was evaluated in subcutaneous, intraocular, and lung metastasis mouse models using the B16F10 melanoma cell line. The optimized polymer PSS0.5-A2B2 formed stable mRNA-loaded nanoparticles (approximately 100 nm) and exhibited time-dependent disassembly under GSH-rich conditions, enabling efficient mRNA release and enhanced IL-12 expression. In vitro, it enhanced cellular uptake, IL-12 expression, and endo/lysosomal escape. In vivo, no significant systemic toxicity was observed. IL-12 mRNA delivery significantly suppressed tumor growth, promoted apoptosis, and reduced metastasis. Combined intravitreal and intravenous administration showed superior antitumor efficacy. This GSH-responsive PBAE platform enables biocompatible intracellular IL-12 mRNA delivery, offering a promising local-systemic combinatorial immunotherapy strategy for melanoma, holding potential promise for UM.

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2026-05-13 | Network-based analysis reveals potential microRNA regulation of oncogenic pathways in SOX10-depleted uveal melanoma.

SOX10 is essential for melanocyte development and maintenance and plays a critical role in uveal melanoma (UM) initiation and progression. While SOX10's transcriptional regulation of protein-coding genes is well characterized, its role on microRNA (miRNA) regulatory landscape in UM remains unexplored. Here, we employed network-based modeling to systematically characterize miRNA regulatory functions following SOX10 depletion in UM. First, we profiled mRNA and miRNA expression levels in SOX10 wild-type and knockdown UM cells. Then, we integrated the transcriptomic data, a UM network, and a Bayesian model to quantify miRNAs' regulatory activities and identify key miRNAs. Subsequently, we employed pathway enrichment analysis combined with literature mining to elucidate the functional roles of identified miRNAs through their target genes and associated signaling pathways in UM. We identified 17 miRNAs that show significant changes in regulatory activities following SOX10 knockdown in UM cells. These miRNAs regulate the expression of genes involved in cancer hallmark pathways, including cell cycle progression, mTORC1 signaling, and fatty acid metabolism. Notably, miR-34a, miR-25, miR-186, and miR-211 have tumor-suppressive potential by targeting genes involved in UM progression and metastasis. Our computational analysis suggests that SOX10 depletion in UM reshapes the miRNA regulatory landscape in a manner potentially consistent with tumor-suppressive activity, requiring experimental validation.

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2026-04-12 | Transforming tumor cells into professional antigen-presenting cells using poly(β-amino ester) nanoparticles to deliver CD80-encoding mRNA.

Effective T-cell activation requires both antigen recognition and co-stimulatory signaling. However, tumor cells typically lack the necessary co-stimulatory molecules, rendering T-cell receptor engagement with tumor antigens insufficient to induce potent anti-tumor immune responses. To overcome this limitation, we converted tumor cells into professional antigen-presenting cell (APC)-like cells by equipping them with the co-stimulatory molecule CD80. Electroporation of melanoma and lung cancer cell lines with CD80-encoding mRNA significantly increased their ability to stimulate tumor-antigen-specific T cells, as indicated by increased activation markers and cytokine secretion. Most importantly, CD80 expression converted melanoma cells into APC-like cells capable of priming and expanding naïve T cells that recognize endogenous tumor antigens. To enable clinical application, we subsequently used poly-(beta aminoester) (pBAE) polymers, which efficiently encapsulate mRNA into nanometric polyplexes. As previously reported, pBAE nanoparticles (NPs) efficiently penetrate plasma membranes and escape endosomal degradation both in vitro and in vivo. Here, we evaluated pBAE NPs encapsulating GFP-encoding mRNA in human cell lines derived from melanoma, lung cancer, leukemia, adenocarcinoma, uveal melanoma, and Merkel cell carcinoma. The pBAE NPs effectively transfected adherent tumor cells, and tumor spheroids in vitro and in ovo. When delivering CD80 mRNA, NPs achieved expression rates of more than 50% in most cell lines, which lasted for at least 72 h. Here as well, nanoparticle-mediated CD80 expression enabled melanoma cells to prime and expand naïve T cells recognizing endogenous tumor antigens. Importantly, T cells primed by CD80-expressing tumor cells were also capable of killing tumor cells that had not been transfected. In line with these findings, T cells stimulated with untransfected tumor cells showed high levels of checkpoint receptors CTLA-4 and PD-1, whereas the expression was significantly lower when using CD80-transfected tumor cells. This proof-of-concept study indicates that conversion of tumor cells into professional APC-like cells with CD80 mRNA is feasible and results in potent anti-tumor CD8+ T-cell responses. With the use of mRNA-loaded pBAEs, the prerequisites for a future application in vivo are given. Therefore, the application of pBAE NPs encapsulating CD80 mRNA to specifically transfect tumor cells presents a new promising strategy for the in vivo treatment of various cancers.

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other

2026-07-14 | Gene therapy for uveal melanoma.

Uveal melanoma (UM) is one of the most prevalent types of intraocular melanomas, which has relatively high morbidity and mortality rates despite being a rare disease. Genetic modifications are one of the prime driving forces behind cellular growth, proliferation, and migration in UM, among which mutation of driver genes (e.g., GNA11, GNAQ, BAP1, EIF1AX, and SF3B1, etc.) and epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNAs) are the key drivers behind oncogenesis. A feasible treatment approach for UM could be gene therapy targeting these genetic mutations and implicated pathways. In this review, current therapeutic options for the treatment of primary and metastatic UM will be briefly discussed in the context of the major driver gene and epigenetic mutations in UM. Primary focus will be on the current state of RNA interference, non-coding RNA, gene editing, gene replacement, and suicide gene therapies for UM, including prospective targeting strategies.

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2026-06-25 | Gene Therapy Strategies for Uveal Melanoma: Adeno-associated Virus Delivery Challenges and Translational Opportunities.

Uveal melanoma is the most common primary intraocular malignancy in adults and remains associated with poor outcomes once metastatic disease develops. Despite advances in local tumour control and molecular prognostication, effective systemic therapies capable of delivering durable benefit are limited. A range of gene-based therapeutic strategies have been explored in uveal melanoma, including immune-based approaches, gene-modified cell therapies and direct gene delivery. While these strategies have yielded important biological insights and modest clinical advances, their broader impact has been constrained by challenges related to delivery, tumour specificity, durability of effect and translational feasibility. This review surveys the current landscape of gene-based therapies investigated in uveal melanoma and synthesises lessons learned from these approaches, with a particular emphasis on the delivery platform as a determinant of therapeutic success. We examine the emerging potential of adeno-associated virus vectors as gene-delivery platforms for uveal melanoma, drawing on their safety profile and capacity for sustained transgene expression. We highlight the need for adaptation beyond native adeno-associated virus serotypes and discuss advances in capsid engineering, targeting strategies and control mechanisms that enable tumour-selective gene delivery. Finally, we consider translational challenges and future directions for integrating targeted adeno-associated virus-based approaches into therapeutic strategies for uveal melanoma.

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2026-05-01 | First-in-human use of recombinant IL-7 to potentiate antigen-specific T cell therapy: a single patient case study.

Clinical trials of adoptive cellular therapy demonstrate that a key characteristic associated with durable responses is in vivo expansion and persistence of transferred T cells. Strategies to develop a less differentiated, stem/memory population in the infusion product and peri-infusional regimens to promote the maintenance of desired T cell states following adoptive transfer would be desirable. Endogenous T cell therapy studies have routinely achieved memory T cells enriched for expression of interleukin (IL)-7 receptor; to eliminate the conventional requirement for immunosuppressive lymphodepletion and its attendant life-threatening toxicities, we performed the first-in-human use of IL-7 in combination with adoptively transferred antigen-specific memory CD8 T cells in a patient with refractory metastatic uveal melanoma. Single-cell immune repertoire profiling of serial peripheral blood sampling revealed substantial in vivo proliferation and expansion of a stem cell memory population in the endogenous T cell therapy product that achieved a >79% predominance of total circulating T cells by 3 weeks post-infusion in this non-lymphodepleted recipient. Although the patient's disease ultimately progressed, these findings demonstrate safety and proof of concept for an IL-7 treatment regimen for expansion of adoptively transferred T cells in vivo and induced memory differentiation in a heavily pretreated patient with refractory solid malignancy.

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2026-04-17 | A CRISPR-Cas13d cancer therapeutic enables selective elimination of uveal melanoma.

Uveal melanoma, the most common eye cancer in adults, remains limited to surgical intervention and radiotherapy, with a dismal survival rate that has not improved in over 50 years. To address this therapeutic impasse, we systematically analyzed public gene expression and CRISPR knockout datasets, identifying RASGRP3 as an essential gene specifically for uveal melanoma. RasGRP3 is uniquely overexpressed and essential for survival in uveal melanoma cells, but dispensable in healthy cells. However, RasGRP3 remains "undruggable" due to its intracellular localization and lack of targetable binding pockets. To overcome this, we developed a CRISPR-Cas13d RNA-targeting therapeutic against RasGRP3, which mediates potent yet selective uveal melanoma killing through two synergistic mechanisms: (1) on-target knockdown of the essential RasGRP3 mRNA, and (2) collateral RNA degradation triggered by the cleavage of overexpressed RasGRP3. When delivered in vitro via optimized lipid nanoparticles loaded with Cas13d mRNA and guide RNA, this strategy eliminated >97% of uveal melanoma cells while sparing healthy cells, including retinal pigment epithelial cells. This approach outperformed conventional Cas9 and siRNA methods in potency without inducing permanent genomic alterations. Our findings establish an RNA-targeting therapeutic for uveal melanoma and a framework for Cas13-based interventions against other "undruggable" cancers.

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2026-03-02 | Recent advances in the molecular genetic mechanisms and immune microenvironment of uveal melanoma.

Given the therapeutic challenges posed by the unique molecular genetic mechanisms and immune-privileged microenvironment of uveal melanoma, this review aims to systematically evaluate the latest research on the molecular genetics and immune microenvironment of uveal melanoma, providing insights for translational research and the development of clinical treatment strategies. In gene therapy, a recombinant adeno-associated viral vector engineered to target the oncogenic GNAQ Q209L mutation achieved single-base-pair precision knockdown, offering a novel approach to overcoming the complex therapeutic challenges posed by downstream signaling in this pathway. Regarding tumor metastasis, BAP1 inactivation induces a low-metabolic state by inhibiting the mTORC1/p70S6K1 pathway, enabling tumor cells to adapt to nutritional stress during metastasis. Concurrently, BAP1 mutations regulate cell adhesion molecules and suppress the nuclear factor-κB pathway, collectively establishing an immunosuppressive microenvironment that drives the highly metastatic nature of uveal melanoma. The predictive value of chromosome 8q amplification was shown to be context-dependent, with high-risk subgroups exhibiting extremely poor prognosis, particularly in BAP1-mutant cases. At the epigenetic level, miR-181a-5p demonstrates therapeutic potential by inducing uveal melanoma apoptosis through targeting GNAQ and AKT3. Clinically, the bispecific T-cell redirection drug Tebentafusp has achieved a major breakthrough in metastatic uveal melanoma immunotherapy. This review systematically elucidates key driver gene mutations, chromosomal abnormalities, epigenetic alterations, and the unique immunosuppressive microenvironment of uveal melanoma, providing new insights into mechanisms of treatment resistance and guiding the development of innovative therapeutic strategies.

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