Living organisms are constantly exposed to endogenous and exogenous agents that have the potential to damage cellular DNA. To survive and prevent the transmission of detrimental mutations to the next generation, cells have evolved multiple DNA damage repair mechanisms to cope with genotoxic agents 1, 2, 3. DNA repair machinery recognizes DNA damage, activates checkpoint signaling, and repairs or bypasses the lesions to maintain overall genomic stability [4].

The DNA damage repair machinery can be categorized into pathways that are responsible for repairing different types of damage (Fig. 1). Nucleotide excision repair (NER) and base excision repair (BER) are involved in repairing single strand breaks (SSBs) or chemical modifications (alkylation, deamination, and oxidation) of DNA bases or replication errors 5, 6. Mismatch repair (MMR) addresses mismatched bases resulting from incorrect nucleotide incorporation 7, 8. The Fanconi anemia (FA) pathway repairs covalent interstrand DNA crosslinks [9]. Double-stranded breaks (DSBs) caused by ionizing radiation or other sources pose a significant threat to genomic integrity and are repaired by homologous recombination (HR), non-homologous end joining (NHEJ), or microhomology-mediated end joining (MMEJ) 1, 10, 11, 12. Translesion synthesis (TLS) is an error-prone back-up repair mechanism that inserts nucleotides at damage sites to avoid replication fork stalling, collapse, and accumulation of deleterious double-strand DNA breaks [13].

Large-scale tumor genome sequencing studies have revealed frequent alterations in DNA repair genes in tumors (Fig. 2). These alterations can be inherited via the germline or acquired sporadically and can directly contribute to tumor genomic instability 14, 15, 16. Mutations that arise within tumors as a result of a DNA repair pathway deficiency can lead to oncogene activation or tumor suppressor gene loss and thereby promote tumorigenesis and tumor evolution [17]. Loss of function of a specific DNA repair pathway often leads to a characteristic patterns of acquired mutations within the tumor, and analysis of these mutational signatures can be used to identify and quantify DNA repair pathway deficiency and genome instability even in the absence of deleterious mutations in known DNA repair genes [18]. Despite the potential to act as a cancer driver, DNA repair pathway deficiency can also represent a therapeutic vulnerability. Loss of specific DNA repair pathways has been shown to confer increased sensitivity to DNA damaging agents such as platinum chemotherapy or DNA repair targeted agents such as poly(ADP-ribose) polymerase (PARP) inhibitors in specific contexts 19, 20.

Immune cells are a critical component of the tumor microenvironment and have complex roles in tumor initiation and progression [21]. A central role of immune cells within the tumor microenvironment involves antigen processing and presentation. If present in the coding regions of genes, mutations that arise due to tumor DNA repair deficiency can lead to the production of altered protein products which are processed through MHC presentation pathways to generate tumor-specific neoantigens on the cell surface. DNA repair deficiency can also lead to the activation of innate immunity when cytosolic DNA activates cGAS/STING signaling, resulting in immune activation via a type I interferon response 22, 23, 24, 25. In this review, we will discuss the impact of specific DNA repair pathway deficiencies on the immune microenvironment and sensitivity to immune checkpoint inhibition.