Unlocking the Therapeutic Potential of DNA-PKcs in Cancer: Comprehensive Insights into Mechanisms and Clinical Applications

Cancer remains one of the most pressing global health challenges, with current therapies often hindered by limited efficacy and the emergence of resistance. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key regulator of DNA repair and cell cycle progression, plays a critical role in maintaining genomic stability, and growing evidence indicates its dysregulation in various cancers, with overexpression frequently associated with aggressive tumor phenotypes. To evaluate DNA-PKcs as a therapeutic target, we systematically analyzed literature from PubMed and Web of Science (2000–2024) using keywords including DNA-PKcs, targeted therapy, DNA repair, and tumor resistance following PRISMA guidelines, with 185 of 1250 initial records meeting inclusion criteria after screening. The review explores the multifaceted roles of DNA-PKcs in tumor biology and resistance mechanisms, evaluates the current landscape of DNA-PKcs inhibitors, including their clinical progress and combination strategies with radiotherapy and chemotherapy, and discusses key determinants of therapeutic efficacy, such as tumor type and mutation status. Additionally, it uniquely integrates emerging insights into the roles of DNA-PKcs in immunomodulation and metabolism, critically assesses next-generation inhibitors, and proposes strategies to address remaining challenges. Through this comprehensive analysis, we highlight the therapeutic potential of DNA-PKcs inhibition as a novel strategy to circumvent treatment resistance, providing innovative insights for optimizing cancer management, especially for aggressive tumor subtypes, thereby advancing drug discovery efforts and paving the way for more effective therapeutic interventions in clinical practice.