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.