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.

Long-wavelength fluorescent carbon quantum dots, as an emerging nanomaterial, could effectively overcome the problems of low detection efficiency, strong antibacterial resistance, and severe imaging interference of traditional methods in the diagnosis and therapy of bacterial infections. Herein, an innovative design of nitrogen and boron codoped orange fluorescent carbon quantum dots (NB-CDs) with both bacterial recognition and binding, long-wavelength fluorescence fast imaging, and broad-spectrum antimicrobial function was developed. The diagnostic and therapeutic integrated nanoplatform was successfully constructed by the solvothermal method using citric acid (CA) as the carbon source, safranine T (ST) as the nitrogen dopant, and 3-aminobenzeneboronic acid (M-APBA) as the boron source. The carbon quantum dots possessed orange fluorescence emission (λ_Em = 581 nm) and high quantum yield (QY) (41.50%), which could effectively avoid the interference of tissue spontaneous short-wavelength fluorescence. The boronic acid group on the surface of the carbon quantum dots is beneficial for covalent binding to bacteria, achieving a synergistic function of antimicrobial and imaging. Meanwhile, the carbon quantum dots exhibited significant antibacterial activity against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (bactericidal rate > 99%), with the minimum bactericidal concentrations (MBC) being 6.90 and 6.13 mg/mL, respectively, and enabled rapid fluorescence labeling imaging of bacteria within 1 h. In this study, an integrated diagnostic and therapeutic system was constructed by combining the binding ability of boric acid groups to bacteria with the optical properties of long-wavelength orange fluorescent carbon quantum dots, providing a new avenue for the development of smart antibacterial materials.

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.

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.

BACKGROUND: Ca ²⁺ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca ²⁺ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca ²⁺ handling and arrhythmia susceptibility. METHODS: There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice). RESULTS: We showed that the ITPR1-W1447G ^+/- and recently reported ITPR1-D2594K ^+/- GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca ²⁺ and voltage imaging in situ in heart slices and Ca ²⁺ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G ^+/- and ITPR1-D2594K ^+/- variants increased the occurrence of stress-induced spontaneous Ca ²⁺ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF. CONCLUSIONS: Our studies in mice and humans reveal that enhanced function of ITPR1 , a well-known movement disorder gene, increases the risk for cardiac arrhythmias.