Macrophage-Induced Senescent Cancer-Associated Fibroblasts Promote SASP-Mediated Chemoresistance in Colorectal Cancer

Abstract Cancer-associated fibroblasts (CAF) play a crucial role in the tumor microenvironment (TME) by influencing tumor progression, metastasis, and therapy resistance. Accumulating evidence suggests that CAFs undergo senescence, which can affect their effects on the TME. In this study, we developed a machine learning–based prediction model, the cellular senescence prediction model, to accurately identify senescent CAFs (sCAF) based on single-cell RNA sequencing data. In colorectal cancer, the abundance of sCAFs strongly correlated with impaired chemotherapy responsiveness and poor prognosis. In preclinical models, including subcutaneous tumors, patient-derived organoids (PDO), PDO xenografts, and orthotopic tumors, sCAFs mediated chemoresistance through the senescence-associated secretory phenotype (SASP), with IL6 and CXCL12 being key contributors. Macrophage-derived IL1B triggered CAF senescence through the IL1B–IL1R1 interaction, promoting the accumulation of sCAFs in tumors. Spatial transcriptomics and multiplex immunohistochemistry revealed the colocalization of IL1B+ macrophages and IL1R1+ sCAFs in the tumor stroma. Functional studies using fibroblast-specific Il1r1 knockout mice further confirmed that macrophage-derived IL1B induces CAF senescence via IL1R1, leading to SASP-driven chemotherapy resistance. These findings highlight the critical role of sCAFs in colorectal cancer chemoresistance and suggest that targeting the IL1B–IL1R1 axis may offer a promising strategy to enhance chemotherapy efficacy in colorectal cancer. Significance: Senescent cancer-associated fibroblasts induced by IL1B-IL1R1 signaling mediated by macrophages secrete SASP factors that impair chemotherapy responsiveness in colorectal cancer, suggesting that stromal senescence could be a therapeutic target.