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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335811 | GEO | 2026/07/01

REPOSITORIES: GEO

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Chemotherapy-induced senescent fibroblasts promote NF-kB-mediated tumor aggressiveness, suppressed by Rofecoxib in gastric cancers

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RNA seq on NEO2734, CFI-400945 or SASP treated cells

Project description:Senolytics, drugs that kill senescent cells, have been proposed to improve the response to pro-senescence cancer therapies. However, lack of broadly acting senolytic drugs remains a challenge. Using inducible CRISPR/Cas9-based genetic screens in different senescent cancer cell models, we identify here loss of the death receptor inhibitor cFLIP as a universal vulnerability of senescent cancer cells. Senescent cancer cells are primed for apoptotic death by NF-kB-mediated upregulation of death receptor DR5 and its ligand TRAIL but are protected from death by increased cFLIP. Activation of DR5 signaling by agonistic antibody, which can be enhanced further by suppression of cFLIP by BRD2 inhibition, leads to efficient killing of all senescent cancer cells tested. We validate this ?one-two punch? cancer therapy by combining pro-senescence therapy with DR5 activation in different animal models.

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