Immunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development.

免疫疗法彻底改变了癌症治疗，并大大改善了多种肿瘤类型的患者治疗效果。然而，大多数患者仍然无法从此类疗法中受益，特别是因为没有预先存在的 T 细胞浸润。DNA 损伤反应 (DDR) 缺陷最近已成为肿瘤免疫原性的重要决定因素。现在，越来越多的证据支持 DDR 靶向疗法可以通过以下方式增加抗肿瘤免疫反应的概念：(1) 通过增加可变性和基因组不稳定性来促进抗原性，(2) 通过激活细胞溶质免疫和免疫原性细胞死亡来增强佐剂性和 ( 3）通过调节控制肿瘤-免疫细胞突触的因素有利于反应原性。在本次审查中，我们讨论了 DDR 和抗癌免疫之间的相互作用，并强调了这种动态相互作用如何有助于塑造肿瘤免疫原性。我们还回顾了可用于研究此类影响的最具创新性的临床前方法，包括最近开发的体外系统。最后，我们强调了利用 DDR-抗癌免疫相互作用带来的治疗机会，重点是早期临床开发中的机会。