Succinate preserves CD8+ T cell fitness to augment antitumor immunity

Abstract

Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8⁺ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8⁺ T cell-mediated immune responses. Sustained succinate exposure promoted CD8⁺ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8⁺ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.

Keywords: SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate.