Reprogramming T cell stemness against cancer

Jiaqi Wang; Ruochen Yan; Dingjiacheng Jia; Shujie Chen

doi:10.1016/j.trecan.2025.09.004

Reprogramming T cell stemness against cancer

Trends Cancer. 2025 Oct 2:S2405-8033(25)00232-8. doi: 10.1016/j.trecan.2025.09.004. Online ahead of print.

Authors

Jiaqi Wang¹, Ruochen Yan¹, Dingjiacheng Jia², Shujie Chen³

Affiliations

¹ Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China; Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
² Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China; Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China. Electronic address: gijdjc@zju.edu.cn.
³ Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China; Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China. Electronic address: chenshujie77@zju.edu.cn.

PMID: 41044011
DOI: 10.1016/j.trecan.2025.09.004

Abstract

Stem-like CD8⁺ T cells - characterized by high-level expression of the transcription factor TCF-1, and known as progenitor exhausted T (T_pex) cells - have emerged as crucial mediators of durable antitumor immunity. These cells demonstrate unique self-renewal capacity, multipotency, and enhanced responsiveness to immune checkpoint blockade therapy. This review synthesizes current understanding of T_pex cell biology, including their defining characteristics, tissue distribution, and functional importance in antitumor immunity. We focus particularly on innovative approaches to preserve and enhance T cell stemness through combination therapies, cytokine signal modulation, epigenetic regulation, tumor microenvironment modification, and microbiota-based interventions. The development of these next-generation immunotherapies targeting T cell stemness represents a transformative frontier in oncology, holding significant promise for improving therapeutic outcomes in cancer patients.

Keywords: TCF-1; cancer; gut microbiota; immune checkpoint blockade; progenitor exhausted T cells; stemness.

Publication types

Review