Pembrolizumab is a humanized IgG4κ monoclonal antibody that selectively binds PD-1 (programmed death receptor-1) on T cells, blocking its interaction with the ligands PD-L1 (CD274) and PD-L2 (PDCD1LG2) and restoring T-cell cytotoxic function. The SDH-specific rationale is grounded in the constitutive pseudohypoxic program driven by succinate accumulation. Noman et al. (J Exp Med 2014, PMID 24493797) demonstrated that HIF-1α directly transcriptionally activates CD274 (PD-L1) via canonical hypoxia-response elements (HREs) in the CD274 promoter, and that this HIF-driven PD-L1 upregulation is the primary mechanism by which hypoxic tumor cells evade cytotoxic T-cell killing. In SDH-deficient tumors, succinate competitively inhibits PHD1/2/3, stabilizing HIF-1α regardless of oxygen tension — creating a constitutive pseudohypoxic state that persistently drives CD274 transcription. The result is a universally elevated tumor-cell PD-L1 expression across all SDH-deficient tumor types (GIST, PPGL, RCC), independent of conventional interferon-γ-driven PD-L1 induction. This HIF-1α → PD-L1 pathway is a mechanistically distinct second arm of immune evasion in SDH-deficient tumors, operating in parallel to and synergistically with the succinate-MCT1-IDO1 axis already represented in this engine (Mechanism 11: AZD3965 and epacadostat entries). Both arms converge on suppression of CD8+ T-cell function in the SDH-deficient tumor microenvironment. Clinical context: The DART trial (NCT02834013, NCI; n=798; Phase 2 basket) tested nivolumab plus ipilimumab (dual PD-1 + CTLA-4 checkpoint blockade) across rare solid tumors including explicit GIST and paraganglioma cohorts — the two predominant SDH-deficient tumor types. NCT02721732 (M.D. Anderson; Phase 2; n=157) evaluated single-agent pembrolizumab in rare tumors including metastatic pheochromocytoma and metastatic paraganglioma. These trials provide proof-of-concept that checkpoint inhibitors are being systematically evaluated in the major SDH-deficient tumor types, though SDH-stratified outcomes have not been reported. Key limitation: No published data report checkpoint inhibitor outcomes stratified by SDH mutation status. CD274 upregulation by HIF-1α has been established in general hypoxia models (Noman et al. 2014) but has not been directly measured in SDH-deficient GIST or PPGL tumor specimens or cell lines. The evidence_score reflects a mechanistically well-grounded but unvalidated-in-SDH hypothesis with supporting clinical trial context. Direct IHC quantification of PD-L1 in SDH-deficient versus SDH-intact GIST and PPGL specimens would be the critical next step before prospective clinical evaluation.