Prostate cancer (PCa) is one of the most prevalent malignancies among men worldwide and a leading cause of cancer-related deaths. As an androgen-dependent tumor of the male reproductive system, PCa initially responds well to androgen deprivation therapy (ADT) and second-generation androgen receptor (AR) antagonists (enzalutamide and apalutamide), which significantly extend progression-free survival. However, Most patients would developed into castration- resistant prostate cancer (CRPC), resulting in the resistant to ADT. The mechanisms driving resistance to novel endocrine therapies exhibit biological complexity, including abnormalities in the AR signaling axis, defects in DNA damage repair, alterations in the tumor microenvironment, and metabolic reprogramming. In recent years, important advances have been made in targeted therapeutic strategies. For instance, PARP inhibitors (olaparib) have demonstrated remarkable efficacy in patients with defects in DNA damage repair, PROTAC technology has shown potential in reversing castration resistance by degrading AR and its variants, thereby countering aberrant activation of the AR signaling pathway. This review systematically elucidates the major resistance mechanisms of CRPC, explores the latest advances in targeted and immunotherapy for CRPC, and envisions the potential of multidisciplinary, multi-target combination therapies to reverse castration resistance in PCa, providing novel therapeutic strategies and targets for CRPC.

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