Adrenal tumor microenvironment: hormone-immune crosstalk, molecular heterogeneity, and immunotherapeutic...

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.