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

Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment (TME) by influencing tumor progression and therapy resistance. Accumulating evidence suggests that CAFs undergo senescence, which can impact their effects on the TME. In this study, we integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multiple preclinical models to explore the mechanisms underlying CAF senescence and its impact on chemotherapy resistance in colorectal cancer (CRC). First, we developed a machine learning-based prediction model, the Cellular Senescence Prediction Model (CSPM), to accurately identify senescent CAFs based on single-cell RNA sequencing data. We used publicly available CRC single-cell cohorts and in-house CRC single-cell data to demonstrate the reliability of the model. By combining in silico analysis and preclinical models, we demonstrated that senescent CAFs induced by IL1B-IL1R1 signaling mediated by macrophages secrete components of the Senescence-Associated Secretory Phenotype (SASP) that impair chemotherapy responsiveness in CRC, suggesting that stromal senescence could be a therapeutic target.