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

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

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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