2026-07-11 | Adrenal tumor microenvironment: hormone-immune crosstalk, molecular heterogeneity, and immunotherapeutic opportunities.
Adrenal tumors comprise a heterogeneous spectrum ranging from functional adenomas to aggressive adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PHEO/PPGL) with metastatic potential. Although traditionally interpreted through hormone excess and oncogenic alterations, current evidence indicates that these tumors are endocrine-shaped immune ecosystems in which hormone secretion, molecular subtype, stromal architecture, metabolic stress, and immune infiltration interact to determine tumor behavior and therapeutic vulnerability. Across subtypes, distinct immune-stromal states emerge: aldosterone-producing adenoma (APA) contains M2-polarized macrophages, specialized endothelial subsets, and metabolic heterogeneity; cortisol-producing adenoma (CPA) is characterized by local glucocorticoid-driven immunosuppression and altered macrophage and T-cell states; ACC is relatively immune-depleted and shaped by glucocorticoid signaling, hypoxia, senescence, and myeloid suppression; and PHEO/PPGL exhibits subtype-dependent angiogenic and immune features linked to catecholamine biology and pseudohypoxia. The strongest human evidence supports cortisol-associated immune remodeling in CPA, macrophage-rich niches in APA, and immune ecotypes in ACC, whereas CAF-mediated immune exclusion, ion-channel-driven immune regulation, and several metabolite-based mechanisms remain largely extrapolative. Clinically, immune checkpoint blockade has shown modest and heterogeneous activity, especially in ACC, where PD-L1 and tumor mutational burden have not consistently predicted response, while selected PPGL subsets may be biologically more permissive. These findings support a model in which adrenal tumors should be classified not only by histology and hormone excess, but also by endocrine-immune microenvironmental states, with implications for biomarker development and rational combination therapies.
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2026-07-02 | ENPP3 CAR T cells combined with CD206 modulation suppress adrenocortical carcinoma.
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis and limited curative treatment options. While chimeric antigen receptor (CAR) T cells have shown some promise in solid tumors, ACC remains largely unexplored in this context. Here, we used patient-derived xenograft (PDX) models of ACC to identify immunotherapeutic targets and develop novel CAR T-cell strategies. Target identification and tumor microenvironment (TME) profiling were conducted using publicly available bulk and single-cell RNA sequencing data from patients with ACC samples. Surface proteomic analysis and flow cytometry of PDXs were conducted to validate antigen candidates. CAR T cells were engineered and tested for cytotoxicity in vitro and in vivo and profiled using flow cytometry and cytokine analysis. We identified ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) as a shared immunotherapy target in 4/7 (57%) ACC PDXs. ENPP3-targeted CAR T-cells eradicated >85% of ENPP3+ ACC cells in vitro but showed attenuated efficacy in PDX mouse models. Restrained ENPP3 CAR T-cell activity correlated with immunosuppressive features of the TME, particularly the presence of CD206+ tumor-associated macrophages (TAMs). Co-treatment with an agent modulating CD206+ TAMs restored CAR T-cell function and improved antitumor responses in ENPP3high and ENPP3low PDX models (difference between mean tumor weights -270.1 mg±117.4; p<0.05). ENPP3 is a novel target for CAR T-cell therapy in ACC. ENPP3 CAR T cells, when combined with CD206 modulation to overcome immune suppression within the TME, have therapeutic efficacy in ACC by mediating robust tumor growth suppression. This combinatorial strategy, which includes CAR T cells alongside therapies that recalibrate immunosuppressive CD206+ TAMs, may be a novel approach for improved immunotherapy of solid cancers beyond ACC.
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2026-06-30 | Gemcitabine and oxaliplatin combination in patients with advanced adrenocortical carcinoma
Abstract Context Adrenocortical cancer (ACC) is a rare, aggressive malignancy with limited treatment options beyond first-line therapy, underscoring the need for effective salvage regimens. Objective To evaluate the clinical activity and safety of gemcitabine and oxaliplatin (GemOx) in advanced ACC. Design Retrospective cohort study conducted from April 2023 to April 2024 with longitudinal follow-up. Setting Single-center tertiary referral cancer center. Patients or Other Participants Fourteen patients with histologically confirmed advanced ACC treated with GemOx were included. Patients were heavily pretreated, with a median of 3 prior systemic therapies (range, 2–9); 43% had hormonally functional tumors. Intervention(s) Gemcitabine (1000 mg/m2 on days 1 and 8) and oxaliplatin (130 mg/m2 on day 1) every 3 weeks until disease progression or unacceptable toxicity. Main Outcome Measure(s) Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate per Response Evaluation Criteria In Solid Tumors 1.1 and treatment-related toxic effects. Results After a median follow-up of 10.7 months (95% CI, 8.5-15.7), median PFS was 3.2 months (95% CI, 0.4-6.0) and OS was 13.0 months (95% CI, 3.6-22.5). Among 13 evaluable patients, 2 (15.4%) achieved partial response, 8 (61.5%) had stable disease, and 3 (23.1%) had progressive disease, yielding a disease control rate of 76.9%. No treatment-related deaths occurred. Conclusions GemOx demonstrated modest clinical activity with manageable safety in heavily pretreated patients with advanced ACC. These findings suggest a potential role for GemOx as a salvage option, though validation in larger prospective studies is needed.
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