Background <p>Treatment failure due to drug resistance has always been a “roadblock” to cancer cure. For a long time, drug resistance research has focused on the nature of the cancer cells themselves; however, more and more studies have found the non-negligible significance of the tumor microenvironment (TME) in cancer malignant progression and therapeutic resistance. Within the TME, cancer-associated fibroblasts (CAFs) represent the most prevalent and highly plastic cells, exerting profound influence on tumor progression.</p> Methods <p>We integrate recent literature and synthesize evidence from both preclinical and clinical studies to elucidate the potential mechanisms by which CAFs contribute to therapeutic resistance and to summarize up-to-date research developments in nanotherapeutic strategies targeting CAFs.</p> Results <p>Emerging findings demonstrate that CAFs substantially contribute to drug resistance by secreting various soluble factors and metabolites, remodeling the extracellular matrix (ECM), and regulating immune responses and cell death. Nanotherapeutic strategies show considerable promise in improving treatment efficacy, while further research is required to facilitate their clinical translation.</p> Conclusions <p>CAFs act as key orchestrators of the drug-resistant TME, positioning them as compelling targets for next-generation anticancer strategies. Moreover, advancing progress in nano-strategies targeting CAFs holds substantial promise for improving clinical outcomes in cancer therapy.</p>