2. Academic Validation
  3. Interferon-driven CAF reprogramming augments immunogenic response to neoadjuvant radiotherapy in colorectal cancer

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

  • Cell Rep Med. 2025 Aug 19;6(8):102251. doi: 10.1016/j.xcrm.2025.102251.
Lili Huang 1,  Weiqing Lu 1,  Ruiyan Wu 1,  Yida Li 2,  Zirui Ou 3,  Jianhua Chen 4,  Yujun Liu 1,  Wang Yang 1,  Weisong Xue 5,  Peiyuan Mu 1,  Ruone Xu 1,  Zhiyuan Zhang 1,  Lijun Shen 1,  Yan Wang 1,  Juefeng Wan 1,  Fan Xia 1,  Zebin Xiao 6,  Hui Zhang 7,  Zhen Zhang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, China.
  • 3 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 5 Department of Gastrointestinal Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University and The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 515100, China.
  • 6 Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China. Electronic address: zbxiao@seu.edu.cn.
  • 7 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. Electronic address: zhui_happy@126.com.
  • 8 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. Electronic address: zhen_zhang@fudan.edu.cn.
PMID: 40730191 DOI: 10.1016/j.xcrm.2025.102251
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.

Keywords

CAFs; IFN/STING pathways; STING agonist; cDC1; radiation.

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