Tong Zheng

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.

Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody–drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment.

More than 70% of cancer patients receive radiotherapy during their treatment, with consequent various side effects on normal cells due to high ionizing radiation doses despite tumor shrinkage. To date, many radioprotectors and radiosensitizers have been investigated in preclinical studies, but their use has been hampered by the high toxicity to normal cells or poor tumor radiosensitization effects. Genistein is a naturally occurring isoflavone found in soy products. It selectively sensitizes tumor cells to radiation while protecting normal cells from radiation-induced damage, thus improving the efficacy of radiotherapy and consequent therapeutic outcomes while reducing adverse effects. Genistein protects normal cells by its potent antioxidant effect that reduces oxidative stress and mitigates radiation-induced apoptosis and inflammation. Conversely, genistein increases the radiosensitivity of tumor cells through specific mechanisms such as the inhibition of DNA repair, the arrest of the cell cycle in the G₂/M phase, the generation of reactive oxygen species (ROS), and the modulation of apoptosis. These effects increase the cytotoxicity of radiation. Preclinical studies demonstrated genistein efficacy in various cancer models, such as breast, prostate, and lung cancer. Despite limited clinical studies, the existing evidence supports the potential of genistein in improving the therapeutic effect of radiotherapy. Future research should focus on dosage optimization and administration, the exploration of combination therapies, and long-term clinical trials to establish genistein benefits in clinical settings. Hence, the unique ability of genistein to improve the radiosensitivity of tumor cells while protecting normal cells could be a promising strategy to improve the efficacy and safety of radiotherapy.