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The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia\u2010inducible factor 2 (HIF2)\u2010mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death\u2010ligand 1 (PD\u2010L1) and HIF2\u03b1 and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD\u2010L1, CTL infiltration, HIF2\u03b1 expression, and the mutational status of\n                    <jats:italic>SDH<\/jats:italic>\n                    genes. Our results show that high PD\u2010L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with\n                    <jats:italic>SDH<\/jats:italic>\n                    mutations and high HIF2\u03b1 protein expression. These data were validated by analysis of mRNA levels of genes expressing PD\u2010L1, CD8, and HIF2\u03b1 in PPGL included in The Cancer Genome Atlas database. Further, PD\u2010L1 and CD8 expression was lower in norepinephrine than epinephrine\u2010secreting PPGL. This\n                    <jats:italic>in silico<\/jats:italic>\n                    analysis also revealed the low PD\u2010L1 or CD8 expression levels in tumors with inactivating mutations in\n                    <jats:italic>VHL<\/jats:italic>\n                    or activating mutations in the HIF2\u03b1\u2010coding gene,\n                    <jats:italic>EPAS1<\/jats:italic>\n                    , which, together with\n                    <jats:italic>SDH<\/jats:italic>\n                    \u2010mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. \u00a9 2022 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6026","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T07:44:12Z","timestamp":1667202252000},"page":"103-114","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype"],"prefix":"10.1002","volume":"259","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3058-7231","authenticated-orcid":false,"given":"Luc\u00eda","family":"Celada","sequence":"first","affiliation":[{"name":"Institute of 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