2. Academic Validation
  3. Succinate preserves CD8+ T cell fitness to augment antitumor immunity

Succinate preserves CD8+ T cell fitness to augment antitumor immunity

  • Immunity. 2025 Aug 9:S1074-7613(25)00326-7. doi: 10.1016/j.immuni.2025.07.017.
Kaili Ma 1,  Hongcheng Cheng 1,  Lin Wang 1,  Han Xiao 2,  Fenghua Liu 1,  Yu Yang 3,  Zhen Xiao 1,  Kun Tang 4,  Shicheng Li 5,  Gang Wang 6,  Minmin Ge 1,  Jiajia Wang 1,  Xiaowei Liu 1,  Hai-Xi Sun 7,  Ziyi Luo 1,  Zhimin Gu 8,  Ping-Chih Ho 9,  Guideng Li 10,  Lianjun Zhang 11
Affiliations

Affiliations

  • 1 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China.
  • 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China; Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215123, China.
  • 4 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China; Institute of Biology and Medical Sciences (IBMS), Soochow University, Suzhou, Jiangsu 215123, China.
  • 5 Center for Cancer Diagnosis and Treatment, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China.
  • 6 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 7 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 8 State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: gzm@ism.pumc.edu.cn.
  • 9 Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. Electronic address: ping-chih.ho@unil.ch.
  • 10 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: lgd@ism.cams.cn.
  • 11 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu 215123, China; Key Laboratory of Synthetic Biology Regulatory Element, Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, Jiangsu 215123, China. Electronic address: zlj@ism.cams.cn.
PMID: 40816269 DOI: 10.1016/j.immuni.2025.07.017
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.

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