Department of Hematology/Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mol Cell. 2023 Mar 2;83(5):660-680. doi: 10.1016/j.molcel.2022.12.031. Epub 2023 Jan 19.
Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.
靶向治疗和免疫疗法已经彻底改变了癌症治疗。然而，癌症逃避免疫系统的能力仍然是有效治疗的主要障碍。与此相关的是，几种靶向 DNA 损伤反应抑制剂（DDRi）正在临床试验中进行测试，并已被证明可以增强抗肿瘤免疫反应。开创性的研究表明，这些药物在具有关键 DNA 修复基因（如 BRCA1/2、BRCA 相关基因、共济失调毛细血管扩张突变（ATM）等）遗传缺陷的泛癌类肿瘤中具有高度疗效。在这里，我们综述了靶向 DDR 抑制的分子后果，从肿瘤细胞死亡到增强抗肿瘤免疫反应的作用。此外，我们还讨论了将靶向 DDRi 与免疫疗法联合使用以增强肿瘤控制的机制和临床原理。我们还回顾了用于患者选择的生物标志物和有前途的新免疫治疗方法，这些方法有望为下一代 DDRi 和免疫治疗联合奠定基础。
