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

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.