干扰素驱动的癌症相关成纤维细胞重编程增强了结直肠癌对新辅助放疗的免疫原性反应。

Interferon-driven CAF reprogramming augments immunogenic response to neoadjuvant radiotherapy in colorectal cancer.

作者信息

Huang Lili, Lu Weiqing, Wu Ruiyan, Li Yida, Ou Zirui, Chen Jianhua, Liu Yujun, Yang Wang, Xue Weisong, Mu Peiyuan, Xu Ruone, Zhang Zhiyuan, Shen Lijun, Wang Yan, Wan Juefeng, Xia Fan, Xiao Zebin, Zhang Hui, Zhang Zhen

机构信息

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Clinical Research Center for Radiation Oncology, Shanghai 20032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai 20032, China.

Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, China.

出版信息

Cell Rep Med. 2025 Aug 19;6(8):102251. doi: 10.1016/j.xcrm.2025.102251. Epub 2025 Jul 28.

DOI:10.1016/j.xcrm.2025.102251

PMID:40730191

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12432360/

Abstract

The efficacy of neoadjuvant radiotherapy (RT) in patients with rectal cancer (RC) is hindered by the plasticity and heterogeneity of cancer-associated fibroblasts (CAFs). However, the underlying mechanisms remain poorly understood. In this study, single-cell RNA sequencing of patients with RC samples revealed a CAF subpopulation characterized by high interferon (IFN) regulatory factor 1 (IRF1) expression. These IFN-licensed CAFs (ilCAFs) are enriched in tumors with enhanced RT responses across various solid tumors, including RC. Mechanistically, IFN gamma (IFN-γ) signaling drives the polarization of ilCAFs, leading to the recruitment of T cells and dendritic cells via CCL4/CCL5 secretion. Activation of IFN-γ/stimulator of IFN genes (STING) signaling reprograms the stroma and augments anti-tumor immunity in both RT-sensitive and RT-resistant colorectal cancer. Silencing STING in CAFs impairs ilCAF enrichment and diminishes tumor sensitivity to RT. Combining STING agonists with RT results in robust tumor control, providing a compelling rationale for clinical translation.

摘要

癌症相关成纤维细胞（CAF）的可塑性和异质性阻碍了新辅助放疗（RT）在直肠癌（RC）患者中的疗效。然而，其潜在机制仍知之甚少。在本研究中，对RC患者样本进行单细胞RNA测序，发现了一个以高干扰素（IFN）调节因子1（IRF1）表达为特征的CAF亚群。这些IFN许可的CAF（ilCAF）在包括RC在内的各种实体瘤中，在放疗反应增强的肿瘤中富集。从机制上讲，IFNγ（IFN-γ）信号驱动ilCAF的极化，导致通过CCL4/CCL5分泌招募T细胞和树突状细胞。IFN-γ/IFN基因刺激物（STING）信号的激活可重新编程基质，并增强放疗敏感和放疗抵抗的结直肠癌中的抗肿瘤免疫。在CAF中沉默STING会损害ilCAF的富集，并降低肿瘤对放疗的敏感性。将STING激动剂与放疗联合使用可实现强大的肿瘤控制，为临床转化提供了令人信服的理论依据。