PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells

  • Sci Immunol. 2026 Jan 23;11(115):eadz7275. doi: 10.1126/sciimmunol.adz7275.
Keling Huang  1  2 ,  Xiaoxue Li  1  2 ,  Wenhua Liang  1  2 ,  Shuyao Wu  2 ,  Youqiong Ye  2 ,  Yan Lu  3 ,  Junke Zheng  3 ,  Weifang Wang  1  2 ,  Qifan Zheng  4 ,  Guo Fu  4 ,  Song Gao  5 ,  Feng Wang  1  2
Affiliations
  • 1. Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2. Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
PMID: 41544148 DOI: 10.1126/sciimmunol.adz7275
Abstract

Immune checkpoint blockade (ICB) has transformed Cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across Cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (TPEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of TPEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of Ptma from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell Oxidative Phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell-mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.

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