<p>Cancer-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment (TME), influencing tumor progression, immune evasion, metastasis, and resistance to therapy. In parallel, emerging evidence underscores the therapeutic potential of targeting CAFs in cancer treatment. While CAFs exhibit significant heterogeneity, with different subtypes contributing to various aspects of tumor biology, including ECM remodeling, immune modulation, and cancer cell proliferation. This complexity presents a challenge in targeting CAFs for effective cancer therapy. Recent advancements in nanotechnology have offered novel strategies for precisely targeting CAFs, thereby modulating the TME to enhance the efficacy of cancer immunotherapy. This review provides a comprehensive overview of CAF biology, the mechanisms through which CAFs contribute to immune suppression and therapy resistance, and the emerging role of CAF-targeted nanomedicines in overcoming these barriers. Key strategies discussed include CAF reprogramming, ECM barrier disruption, and the targeting of immune checkpoints, all aimed at reshaping the TME into a more immune-permissive environment. However, despite promising preclinical results, several challenges remain, such as optimizing nanoparticle delivery, overcoming CAF-related drug resistance, and addressing the complex immunosuppressive networks within the TME. Future research should focus on the development of more targeted and personalized nanomedicine approaches, improving CAF-specific drug delivery systems, and better understanding the dynamic interactions between CAFs and the immune system. Our review highlights the current advances in CAF-targeted nanomedicine and underscores the importance of these strategies in advancing cancer immunotherapy. Ultimately, overcoming the challenges associated with CAF-targeted therapies could significantly improve clinical outcomes and pave the way for more effective, individualized cancer treatments.</p>