SDH loss creates an immunosuppressive tumor microenvironment through two distinct succinate-dependent mechanisms: (1) extracellular succinate is directly taken up by tumor-infiltrating T cells via MCT1 (SLC16A1), impairing TCA-cycle glucose oxidation in T cells and suppressing IFN-γ secretion and degranulation — demonstrated in human CD4+/CD8+ T cells at tumor-associated succinate concentrations (Gudgeon et al., Cell Rep 2022, PMID 35977513), with RNA-seq of SDH-deficient pheochromocytoma/paraganglioma confirming profound in-vivo IFN-γ signaling suppression; and (2) the pseudohypoxic HIF-1α program drives upregulation of IDO1 (indoleamine 2,3-dioxygenase 1), the rate-limiting enzyme in the tryptophan→kynurenine degradation pathway, with aberrant kynurenine pathway activity confirmed in metastatic SDHB-driven PPGL by multi-omics (PMID 42230482). Together these mechanisms create a profoundly T-cell-hostile TME in SDH-deficient tumors.

Unvalidated SDH research hypothesis: succinate-associated pseudohypoxia might alter CD155/PVR expression and TIGIT checkpoint activity. Neither this chain nor selective benefit from TIGIT blockade is established in SDH-deficient cancers by the sources reviewed. No SDH-specific tiragolumab result was verified in this review. This is a research lead, not a treatment recommendation. Eskandari et al. (PMID 42160101, Effect of HIF-1α and LDHA Blockade on Gene Expression of Tumor Immune Evasion in Myeloid Leukemia Cell Lines) treated HL-60 and K-562 leukemia cells with silibinin or sodium oxamate for 48 hours. Silibinin reduced CD155 mRNA in HL-60 but not K-562; sodium oxamate did not significantly change CD155 expression. The authors call these pharmacologically induced associations, not direct evidence of HIF-1α or LDHA pathway blockade. They do not establish CD155 protein changes, immune-cell function, direct HIF-promoter binding or an SDH-specific dependency. Completed Phase 3 SKYSCRAPER-01 (NCT04294810) tested tiragolumab plus atezolizumab against placebo plus atezolizumab in previously untreated PD-L1-high advanced NSCLC. The final publication (PMID 42507968, J Clin Oncol 2026) reported no statistically significant progression-free or overall survival benefit under the study criteria. Combination results do not establish tiragolumab monotherapy benefit or SDH-specific efficacy.

TIGIT is the direct target of tiragolumab; CD155/PVR is its ligand, not the antibody target. The TIGIT-tiragolumab complex and UniProt identity are documented by RCSB 8JEO. Unvalidated SDH research hypothesis: succinate-associated pseudohypoxia might alter CD155/PVR expression and TIGIT checkpoint activity. Neither this chain nor selective benefit from TIGIT blockade is established in SDH-deficient cancers by the sources reviewed. No SDH-specific tiragolumab result was verified in this review. This is a research lead, not a treatment recommendation. Eskandari et al. (PMID 42160101, Effect of HIF-1α and LDHA Blockade on Gene Expression of Tumor Immune Evasion in Myeloid Leukemia Cell Lines) treated HL-60 and K-562 leukemia cells with silibinin or sodium oxamate for 48 hours. Silibinin reduced CD155 mRNA in HL-60 but not K-562; sodium oxamate did not significantly change CD155 expression. The authors call these pharmacologically induced associations, not direct evidence of HIF-1α or LDHA pathway blockade. They do not establish CD155 protein changes, immune-cell function, direct HIF-promoter binding or an SDH-specific dependency. Completed Phase 3 SKYSCRAPER-01 (NCT04294810) tested tiragolumab plus atezolizumab against placebo plus atezolizumab in previously untreated PD-L1-high advanced NSCLC. The final publication (PMID 42507968, J Clin Oncol 2026) reported no statistically significant progression-free or overall survival benefit under the study criteria. Combination results do not establish tiragolumab monotherapy benefit or SDH-specific efficacy. Sources: https://pubmed.ncbi.nlm.nih.gov/42160101/ ; https://pmc.ncbi.nlm.nih.gov/articles/PMC13535869/ ; https://pubmed.ncbi.nlm.nih.gov/42507968/ ; https://clinicaltrials.gov/study/NCT04294810 ; https://www.rcsb.org/structure/8JEO ; https://db.antibodysociety.org/db0/1038 .

UniProt: Q495A1