On November 6, 2025, the research team led by Professor Zemin Zhang from Biomedical Pioneering Innovation Center (BIOPIC) at Peking University / Chongqing Medical University, in collaboration with partners, published an article entitled "Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer" in Cancer Cell . The study systematically uncovered how total neoadjuvant therapy (TNT) reshapes the tumor immune microenvironment in locally advanced rectal cancer (LARC), identifying the interaction between CD8⁺ T cells and endothelial cells as a key driver of TNT’s clinical efficacy. This work provides a new framework for optimizing rectal cancer treatment strategies and deepens our understanding of the complex mechanisms underlying neoadjuvant chemoradiotherapy.

Figure 1. Research strategy and key findings

Colorectal cancer ranks third in incidence and second in mortality among global malignancies, with approximately 85% of patients exhibiting microsatellite stability and proficient mismatch repair (pMMR). These patients have low tumor mutational burden and weak immunogenicity, leading to poor responses to immune checkpoint inhibitors. TNT has emerged as a promising treatment to improve complete response rates, while its cellular and molecular mechanisms, particularly how it modulates immune components and intercellular crosstalk at the single-cell level, remain unclear.

To address this gap, the research team analyzed 92 samples (including tumor tissue and blood) from 26 LARC patients before and after neoadjuvant treatments. By integrating single-cell RNA sequencing, single-cell T cell receptor sequencing, spatial transcriptome sequencing, multiplex immunofluorescence, and in vitro functional assays, they constructed a dynamic atlas of the tumor immune microenvironment during TNT. Comparative analysis of neoadjuvant chemotherapy (nCT), intermediate neoadjuvant radiotherapy (nRT), and TNT revealed three key findings:

TNT significantly enhanced anti-tumor immunity. Compared to nCT and nRT, TNT increased the infiltration of IFNG⁺CD8⁺ T cells (a cell subset with potent anti-tumor activity) in tumor tissues and upregulated IFNG signaling in the tumor microenvironment. Notably, peripheral blood IFNG signal intensity served as a potential biomarker for predicting complete response, offering a convenient clinical tool for efficacy assessment.

ACKR1⁺ endothelial cell (EC) subset acted as a critical bridge for immune recruitment. The study identified ACKR1⁺ ECs as key mediators of CD8⁺ T cell recruitment from peripheral blood into the tumor microenvironment. After TNT, these cells exhibited enhanced recruitment capacity, improved antigen-presenting function, and T cell activation ability—with in vitro experiments confirming antigen-specific activation of CD8⁺ T cells.

A reciprocal interaction loop amplified anti-tumor effects. TNT upregulated IFNG signaling and IFNG receptor ( IFNGR ) expression in ACKR1⁺ ECs, indicating regulation by IFNγ secreted by IFNG⁺CD8⁺ T cells. This formed a functional loop: IFNG⁺CD8⁺ T cells modulated ACKR1⁺ ECs, which in turn recruited and activated more CD8⁺ T cells, continuously amplifying the anti-tumor immune response and improving tumor killing efficiency.

The study was co-authored by Academician Zemin Zhang (BIOPIC, Peking University / Chongqing Medical University), Professor Peirong Ding (Sun Yat-sen University Cancer Center), Associate Professor Linnan Zhu (BIOPIC, Peking University), Professor Sijin Cheng (Chongqing Medical University), and Professor Qianqian Gao (Chongqing Medical University). Professor Qianqian Gao (Chongqing Medical University), PhD candidate Xinnan Ling (BIOPIC / School of Life Sciences, Peking University), Dr. Leen Liao (Sun Yat-sen University Cancer Center), Dr. Fei Tang (School of Life Sciences, Peking University), and Dr. Yujia Jiang (BGI Research, Hangzhou) are co-first authors. This research was supported by Shenzhen Bay Laboratory, the National Key Research and Development Program of China, and the National Natural Science Foundation of China.

Paper link: https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00449-0