Nanomedicine Targeting Cancer-Associated Fibroblasts in Prostate Cancer: From Biological Mechanisms to Integrated Theranostic Strategies

Abstract: Prostate cancer (PCa) is the second most common malignancy in men worldwide. Advanced stages are characterized by tumor heterogeneity, metastasis, and resistance to androgen deprivation therapy and chemotherapy. Cancer-associated fibroblasts (CAFs), the predominant stromal cells in the PCa tumor microenvironment (TME), critically drive tumor progression, metastasis, and therapeutic resistance. Nanomedicine represents a transformative strategy for targeting CAFs. It leverages engineered nanomaterials to achieve precise drug delivery, improved bioavailability, and multimodal theranostic capabilities, which integrate diagnosis with therapy. This review comprehensively examines advances in nanomaterial-based strategies for CAF-targeted therapy in PCa. We first delineate the biology of CAFs in PCa, encompassing their origins, activation mechanisms, key markers (e.g, α-SMA and FAP), phenotypic heterogeneity, and intricate crosstalk with cancer cells, immune cells, and the extracellular matrix (ECM). We then evaluate nanomaterial-based targeting strategies and therapeutic modalities, including CAF depletion, reprogramming, and extracellular matrix remodeling, for the treatment of PCa. Subsequently, we discuss CAF-targeted nanoplatforms for theranostics, including molecular imaging probes (e.g., 68 Ga-FAPI) and image-guided delivery systems that integrate precise diagnosis with therapy. Finally, we address key challenges, particularly CAF heterogeneity and nanomaterial biosafety, and outline future directions, including gene-editing integration, multi-stimuli-responsive systems, and synergistic immunotherapy combinations. Collectively, this review underscores the transformative potential of integrating CAF biology with nanotechnology to overcome therapeutic resistance in PCa and advance precision oncology. Keywords: cancer-associated fibroblasts, prostate cancer, tumor microenvironment, nanomedicine, diagnostics and therapeutics, targeted therapy