Overcoming radioresistance in prostate cancer by targeting DNA damage repair

Prostate cancer (PCa) remains one of the most prevalent malignancies among men, with radiotherapy (RT) serving as a cornerstone of treatment. However, radioresistance (RR) remains a major clinical challenge, contributing to treatment failure, disease recurrence, and poor prognosis. A major driver of RR is the enhanced DNA damage repair (DDR) ability of PCa cells, which allows them to evade RT-induced cell death. This review critically examines the molecular basis of RR in PCa, with particular focus on DDR pathways. We address the role of key genetic alterations, including mutations in BRCA2, ATM, and PARP1, on RT response, highlighting their potential as therapeutic targets to overcome RR. We further explore the interplay of DDR inhibition with androgen receptor (AR) signaling and its ability to potentiate antitumor immunity through activation of the cGAS-STING pathway, type I interferon production, and regulation of immune checkpoints. By leveraging insights into DDR mechanisms and therapeutic opportunities, this review provides a comprehensive perspective to enhance RT efficacy and improve clinical outcomes in PCa patients.