Clark Curtis A, Yang Eddy S
Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
J Immunother Precis Oncol. 2022 Dec 2;6(1):31-49. doi: 10.36401/JIPO-22-15. eCollection 2023 Feb.
Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic "hallmarks of cancer" processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nucleic acids, has enhanced our understanding of the genetic and epigenetic molecular mechanisms in tumorigenesis and will become fundamental to precisely target tumors and achieve cancer control. With the successes of poly(ADP-ribose) polymerase inhibitors (PARPi) and immunotherapies, the intersection of DDR molecular machinery and corresponding antitumor immune response has gained much interest with a focus on achieving therapeutic synergy using DNA damage-targeting agents and immunotherapy. In this review, we provide a bench-to-bedside overview of the fundamentals of DDR signaling and repair as they relate to cancer therapeutic strategies including novel DDR-targeting agents. We also discuss the underlying mechanisms that link DDR signaling to antitumor immunity and immunotherapy efficacy, and how this knowledge can be used to improve precision medicine approaches in the treatment of cancer.
癌症的表现是一个多步骤过程，涉及各种基因和表观遗传变化的积累，这些变化导致致癌的“癌症标志”过程，包括基因组不稳定。利用癌症中异常的DNA损伤反应（DDR）机制在一定程度上是许多治疗策略的目标，最近的证据支持靶向DDR在调节肿瘤免疫微环境以增强免疫治疗反应中的作用。改进的癌症分析，包括肿瘤组织以及循环核酸的下一代和全基因组突变测序，增强了我们对肿瘤发生中基因和表观遗传分子机制的理解，并将成为精确靶向肿瘤和实现癌症控制的基础。随着聚（ADP-核糖）聚合酶抑制剂（PARPi）和免疫疗法的成功，DDR分子机制与相应抗肿瘤免疫反应的交叉点引起了广泛关注，重点是使用DNA损伤靶向药物和免疫疗法实现治疗协同作用。在这篇综述中，我们提供了一个从实验室到临床的DDR信号传导和修复基础知识的概述，这些知识与包括新型DDR靶向药物在内的癌症治疗策略相关。我们还讨论了将DDR信号传导与抗肿瘤免疫和免疫治疗疗效联系起来的潜在机制，以及如何利用这些知识来改进癌症治疗中的精准医学方法。
