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.
癌症仍是全球最紧迫的健康挑战之一，现有疗法常因疗效有限及耐药性出现而受限。DNA依赖性蛋白激酶催化亚基（DNA-PKcs）作为DNA修复与细胞周期进程的关键调控因子，在维持基因组稳定性中发挥核心作用。越来越多的证据表明其在多种癌症中存在失调现象，其过表达常与侵袭性肿瘤表型相关。为评估DNA-PKcs作为治疗靶点的潜力，我们依据PRISMA指南，系统检索了PubMed和Web of Science数据库（2000–2024年），使用DNA-PKcs、靶向治疗、DNA修复、肿瘤耐药等关键词，经筛选后从1250篇初始文献中纳入185篇符合标准的研究。本综述深入探讨了DNA-PKcs在肿瘤生物学及耐药机制中的多重作用，评估了当前DNA-PKcs抑制剂的发展现状（包括临床进展及其与放化疗的联合策略），并讨论了肿瘤类型与突变状态等疗效关键决定因素。此外，本文创新性地整合了DNA-PKcs在免疫调节与代谢调控中的新兴发现，批判性评估了新一代抑制剂，并提出应对现存挑战的策略。通过全面分析，我们揭示了抑制DNA-PKcs作为克服治疗耐药性新策略的治疗潜力，为优化癌症（尤其是侵袭性肿瘤亚型）管理提供创新见解，从而推动药物研发进程，为临床实践中更有效的治疗干预铺平道路。
肿瘤(癌症)患者之家