Immunomodulatory actions of catecholamines, cluster-specific signaling pathways, and metabolites in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms with an exceptionally high genetic contribution, often driven by single high-penetrance mutations. Approximately one third of patients harbor germline mutations and another third carry somatic driver mutations, allowing stratification into three molecular clusters: pseudohypoxia-related (cluster 1), kinase signaling-related (cluster 2) and Wnt-signaling-related (cluster 3). These clusters differ in catecholamine secretion, malignancy, and metastatic behavior. Although PPGLs have long been viewed as immunologically 'cold' due to their low neoantigen load and limited T cell infiltration, recent studies show a more complex immune landscape, with differences observed between indolent and metastatic tumors, and between genomic clusters. The interaction between the tumor and immune system is, in general, closely associated with tumorigenesis and disease prognosis, with both the innate and adaptive immune system playing pivotal roles. This review summarizes how tumor-derived catecholamines and cluster-specific genetic drivers and metabolic programs are able to orchestrate immune modulation in PPGL. Within clusters of PPGL, distinct metabolic and signaling alterations such as pseudohypoxia, tricarboxylic acid cycle oncometabolites, and aberrant kinase and B-catenin signaling shape both the tumor microenvironment and systemic immune response. We highlight therapeutic opportunities together with approaches that harness or reprogram innate immune memory. Recognizing PPGL as metabolically and immunologically stratified tumors may enable rational, personalized combination therapies for patients with inoperable, recurrent or metastatic disease, and might explain the heterogeneous response to immunotherapy currently observed.