Transcriptional subtypes on immune microenvironment and predicting postoperative recurrence and metastasis in human pheochromocytoma and paraganglioma.

Human pheochromocytomas and paragangliomas (PPGLs) exhibit substantial molecular and immune heterogeneity, complicating risk assessment and treatment. Here, we define three distinct tumor transcriptional subtypes (C1, C2, and C3) in a clinically annotated cohort of PPGL patients through integrative transcriptomic and immunogenomic profiling. C1 is characterized by hypoxia-driven pathways and an immunosuppressive microenvironment, correlating with poor prognosis. C2 exhibits a highly inflamed immune landscape with robust CD8(+) T cell infiltration, suggesting potential sensitivity to immunotherapy. C3 is enriched in metabolic reprogramming pathways and displays intermediate clinical outcomes. Genetic analysis reveals subtype-specific mutational patterns, with pseudohypoxic driver mutations (SDHB, VHL, SDHA, and SDHD) predominant in C1 and C3, while kinase pathway alterations (NF1 and RET) define C2. Single-nucleus RNA sequencing of human PPGL tumors further delineates immune ecosystem diversity. Notably, we identify ANGPT2, PCSK1N, and GPX3 as key subtype-specific biomarkers, with ANGPT2 driving tumor progression in C1 and emerging as a potential therapeutic target. Our findings provide a refined molecular classification integrating immune and genomic features in human PPGLs, offering a framework for improved prognostication and precision therapies in this rare neuroendocrine tumor type.