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

作者：Qianqian Gao, Xinnan Ling, Leen Liao, Fei Tang, Yujia Jiang, Shishang Qin, Wenhong Hou, Wei Zhou, Lijuan Jiang, Chunman Xiao, Yufei Bo, Yuhui Miao, Hai-xi Sun, Ruoyao Wang, Kezhuo Yu, Qiaoqi Sui, Shijie Hao, Wei-Jian Mei, Dongfang Wang, Xiuqing Zhang, Sijin Cheng, Linnan Zhu, Peirong Ding, Zemin Zhang · 发表于：Cancer Cell · 年份：2025 · DOI：10.1016/j.ccell.2025.10.008 · 被引用次数：8 · 研究领域：Cancer Immunotherapy and Biomarkers、Single-cell and spatial transcriptomics、Colorectal Cancer Surgical Treatments

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. • Multi-omics unveil distinct tumor microenvironment shifts in neoadjuvant therapies • IFNG + CD8 + Tem cells and ACKR1 + endothelial cells increase following TNT • ACKR1 + ECs recruit and activate CD8 + T cells, and an IFNG - IFNGR loop forms post TNT • IFNG + CD8 + T cell abundance and PBL IFNG signals mark response to TNT Gao et al. characterize the tumor microenvironment dynamics following total neoadjuvant therapy (TNT) in locally a...