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Colorectal cancer (CRC) remains a significant global health burden, being the third most diagnosed cancer and second leading cause of cancer-related mortality. While there have been advances in early detection and treatment of CRC, outcomes for patients with advanced or metastatic disease remain poor due to high rates of therapy resistance and disease recurrence. Cancer-associated fibroblasts (CAFs) play a crucial role in the progression of CRC by actively modulating the tumor microenvironment (TME). CAFs differ from normal fibroblasts in that they remain persistently activated and acquire a myofibroblast-type behavior due to various signaling pathways, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and interleukins in CRC. One of the most important ways that CAFs mediate their pro-tumorigenic effect is through the release of exosomes. Exosomes are small extracellular vesicles that carry a broad range of cargo, including proteins, lipids, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and metabolites. These CAF-derived exosomes contribute to robust intercellular communication within the tumor microenvironment (TME), reprogramming both cancer cells and the remaining stromal elements. Also, particular emphasis is placed on how CAF-derived exosomes modulate cellular responses to cytotoxic agents, containing 5-fluorouracil, oxaliplatin, irinotecan, and radiotherapy. These exosomes alter DNA damage responses, ferroptosis, apoptosis, oxidative stress, and survival signaling, thereby reshaping the toxicity profile of anticancer treatments. Understanding these exosome-mediated mechanisms is critical for overcoming chemoresistance and radiosurvival in CRC.