Immune Subtypes of PPGL: Genomic Determinants and Therapeutic Implications

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms with significant hereditary predisposition and metastatic potential for which systemic treatment options remain limited. Although characterized as immunologically inert tumors, emerging evidence reveals a biologically meaningful diversity of immune subtypes whose distribution is tightly coupled to genomic subtype, metabolic phenotype, and clinical behavior. PPGLs are classified into three major transcriptional clusters, pseudohypoxic, kinase signaling, and WNT-altered, each associated with a characteristic tumor microenvironment (TME). Pseudohypoxic tumors, driven by SDHx and related alterations, display immunosuppressive microenvironments enriched in fibroblast-like perivascular cells and shaped by succinate accumulation and HIF-2α-mediated signaling, while kinase signaling tumors preferentially associate with immune-enriched profiles. MAML3 fusion-positive tumors represent a distinct immunological exception, combining adaptive PD-L1 overexpression with CD8+ T cell and NK cell infiltration and a higher predicted neoantigen burden, whose functional relevance remains to be established. Secondary genomic events, particularly ATRX mutations, TERT activation, and somatic copy number alterations, further modulate immune contexture and metastatic risk. Pan-cancer immune classification frameworks identify lymphocyte-depleted subtypes as predominant in PPGLs, with a progressive shift toward greater immunosuppression in metastatic disease. These findings have direct therapeutic implications: the HIF-2α inhibitor belzutifan has demonstrated meaningful activity in pseudohypoxic tumors and may carry immunomodulatory effects, while MAML3 fusion-positive and immune-enriched kinase signaling tumors may represent the subset most amenable to immune checkpoint inhibition. Translating this biological complexity into clinical benefit will require molecularly stratified trials, standardized immune profiling, and expanded international collaborative efforts.