Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer

  • Cancer Cell. 2025 Dec 8;43(12):2282-2297.e9. doi: 10.1016/j.ccell.2025.10.008.
Qianqian Gao  1 ,  Xinnan Ling  2 ,  Leen Liao  3 ,  Fei Tang  2 ,  Yujia Jiang  4 ,  Shishang Qin  2 ,  Wenhong Hou  5 ,  Wei Zhou  5 ,  Lijuan Jiang  6 ,  Chunman Xiao  5 ,  Yufei Bo  2 ,  Yuhui Miao  6 ,  Hai-Xi Sun  7 ,  Ruoyao Wang  5 ,  Kezhuo Yu  2 ,  Qiaoqi Sui  3 ,  Shijie Hao  4 ,  Weijian Mei  3 ,  Dongfang Wang  2 ,  Xiuqing Zhang  8 ,  Sijin Cheng  9 ,  Linnan Zhu  10 ,  Peirong Ding  11 ,  Zemin Zhang  12
Affiliations
  • 1. Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China. Electronic address: [email protected].
  • 2. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 3. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 4. State Key Laboratory of Genome and Multi-omics Technologies, Key Laboratory of Spatial Omics of Zhejiang Province, BGI Research, Hangzhou 310030, China.
  • 5. Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 6. Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China.
  • 7. BGI Research, Shenzhen 518083, China; BGI Research, Beijing 102601, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 8. BGI Research, Shenzhen 518083, China.
  • 9. Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
  • 10. Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: [email protected].
  • 11. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 12. Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China; Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: [email protected].
PMID: 41202810 DOI: 10.1016/j.ccell.2025.10.008
Abstract

Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal Cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome Sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG+CD8+ effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8+ T cells is correlated with the enrichment of the ACKR1+ endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8+ T cells, acquire an enhanced ability for presenting antigens and activating CD8+ T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8+ T cells and ECs after TNT.

Keywords
CD8(+) T cells; IFNγ; endothelial cells; feedback loop; neoadjuvant chemoradiotherapy; rectal cancer; total neoadjuvant therapy.
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