2. Academic Validation
  3. Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer

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

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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