Regulatory T cell-derived TGF-β signaling governs the differentiation and maintenance of tumor-infiltrating bystander CD8+ T cells

  • Cell Rep. 2026 Mar 27;45(4):117189. doi: 10.1016/j.celrep.2026.117189.
Yao Lin  1 ,  Shuai Yue  2 ,  Ding Qiu  3 ,  Junjian He  4 ,  Yang Yang  5 ,  Shusen Ye  3 ,  Wenwen Xi  4 ,  Hairu Wang  4 ,  Chunyang Xie  5 ,  Texi Liang  5 ,  Kaiyi Li  3 ,  Xiaofan Yang  5 ,  Yaxing Hao  4 ,  Yuqing Li  6 ,  Yi Yang  7 ,  Teming Li  8 ,  Song Wu  9 ,  Lilin Ye  10 ,  Xiangyu Chen  11
Affiliations
  • 1. Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518116, China; Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen 518060, China.
  • 2. Cancer Center, Daping Hospital and Army Medical Center of PLA, Army Medical University (Third Military Medical University), Chongqing 400020, China.
  • 3. Institute for Immunology and Pathogenesis, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 4. Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 5. Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China.
  • 6. Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518116, China.
  • 7. Department of Rheumatology and Immunology, Center for Immune Ageing and Rejuvenation, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 8. Department of General Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing 400037, China. Electronic address: [email protected].
  • 9. Department of Urology, South China Hospital, Medical School, Shenzhen University, Shenzhen 518116, China. Electronic address: [email protected].
  • 10. Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: [email protected].
  • 11. Department of Rheumatology and Immunology, Center for Immune Ageing and Rejuvenation, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
PMID: 41903139 DOI: 10.1016/j.celrep.2026.117189
Abstract

While indispensable for antitumor immunity, tumor-specific CD8+ T cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME). In contrast, bystander memory CD8+ T (TBYS) cells that recognize pathogen-derived antigens but not tumor antigens are abundant in tumors and maintain polyfunctional effector capacity, yet their differentiation and maintenance mechanisms remain unclear. Here, we demonstrate that CD8+ TBYS cells comprise a heterogeneous population of TCM, TEM, and TRM subsets defined by distinct chromatin accessibility and transcriptional programs. These subpopulations follow a progressive TCM→TEM→TRM differentiation trajectory during tumor progression, with TRM cells exhibiting superior tissue retention and ultimately dominating the TBYS pool. We further identify TGF-β-derived from regulatory CD4+ T cells as the central instructor of this hierarchical differentiation, which promotes TBYS cell accumulation through suppression of KLF2. Our study elucidates a key mechanism of TBYS cell differentiation and maintenance, providing a foundation for the improved immunotherapies targeting this population.

Keywords
CP: cancer; CP: immunology; KLF2; TGF-β; bystander T cell; regulatory T cell; tissue-resident memory T cell.
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