Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting the DNA damage response in immuno-oncology: developments and opportunities

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Genome integrity-related dysfunctions and molecular determinants of cytosolic immunity.
Fig. 2: The DNA damage response shapes the tumour–immune cell interface.
Fig. 3: Therapeutic strategies to exploit the DNA damage response–immunity interplay in the clinic.

References

  1. 1.

    Lord, C. J. & Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017). This study reports that MMR deficiency results in increased tumour immunogenicity and response to anti-PD1/anti-PDL1 therapy regardless of the cancer type.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Mouw, K. W., Goldberg, M. S., Konstantinopoulos, P. A. & D’Andrea, A. D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 7, 675–693 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Chabanon, R. M., Soria, J. C., Lord, C. J. & Postel-Vinay, S. Beyond DNA repair: the novel immunological potential of PARP inhibitors. Mol. Cell. Oncol. 6, 1585170 (2019).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Upadhaya, S. et al. Combinations take centre stage in PD1/PDL1 inhibitor clinical trials. Nat. Rev. Drug Discov. 20, 168–169 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Chen, D. S. & Mellman, I. Oncology meets immunology: The cancer-immunity cycle. Immunity 39, 1–10 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. 9.

    Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016). This article shows that, beyond TMB, intratumour heterogeneity and neoantigen clonality are critical determinants of the antitumour efficacy of ICI.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Nelson, R. W. et al. T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 42, 95–107 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Wang, S. et al. Analyzing the effect of peptide-HLA-binding ability on the immunogenicity of potential CD8+ and CD4+ T cell epitopes in a large dataset. Immunol. Res. 64, 908–918 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Leng, Q., Tarbe, M., Long, Q. & Wang, F. Pre-existing heterologous T-cell immunity and neoantigen immunogenicity. Clin. Transl. Immunol. 9, e01111 (2020).

    Article  Google Scholar 

  14. 14.

    De Mattos-Arruda, L. et al. Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group. Ann. Oncol. 31, 978–990 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Anagnostou, V. et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 7, 264–276 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Rajasagi, M. et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124, 453–462 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Sahin, I. H. et al. Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms. Br. J. Cancer 121, 809–818 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Guan, J. et al. MLH1 deficiency-triggered DNA hyperexcision by exonuclease 1 activates the cGAS-STING pathway. Cancer Cell 39, 109–121.e5 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Lu, C. et al. DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity. Cancer Cell 39, 96–108.e6 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). Following data described by Snyder et al. (2014) in patients with melanoma treated with anti-CTLA4, this study identifies that response to anti-PD1 in patients with NSCLC correlates with higher TMB, higher TNB and molecular signatures associated with DNA damage.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Howitt, B. E. et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 1, 1319–1323 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Mehnert, J. M. et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J. Clin. Invest. 126, 2334–2340 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Johanns, T. M. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 6, 1230–1236 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non–small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Seiwert, T. Y. et al. Biomarkers predictive of response to pembrolizumab in head and neck cancer (HNSCC). Cancer Res. 78 (13 Suppl.), abstract LB-339 (2018).

  32. 32.

    Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020). This prospective multicohort study validates the positive correlation between TMB of ten or more mutations per megabase and better response to the anti-PD1 pembrolizumab in a cancer histology-agnostic fashion.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    McAlpine, J. N. et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod. Pathol. 25, 740–750 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Nolan, E. et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci. Transl. Med. 9, eaal4922 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Connor, A. A. et al. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma. JAMA Oncol. 3, 774–783 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Wu, Y. M. et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 173, 1770–1782.e14 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Viel, A. et al. A specific mutational signature associated with DNA 8-oxoguanine persistence in MUTYH-defective colorectal cancer. EBioMedicine 20, 39–49 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Melton, D. W. et al. Cells from ERCC1-deficient mice show increased genome instability and a reduced frequency of S-phase-dependent illegitimate chromosome exchange but a normal frequency of homologous recombination. J. Cell Sci. 111, 395–404 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Aiello, M. M. et al. Excision repair cross complementation group 1 (ERCC-1) gene polymorphisms and response to nivolumab in advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol. 35, 3032 (2017).

    Article  Google Scholar 

  40. 40.

    Chabanon, R. M. et al. PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer. J. Clin. Invest. 129, 1211–1228 (2019). This study describes for the first time that various clinical PARP inhibitors selectively elicit a cGAS–STING-mediated innate immune response in the molecular contexts where they also trigger synthetic lethality.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    George, J. et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin. Cancer Res. 19, 3474–3484 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Auslander, N., Wolf, Y. I. & Koonin, E. V. Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability. Nat. Commun. 11, 1234 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Chabanon, R. M., Morel, D. & Postel-Vinay, S. Exploiting epigenetic vulnerabilities in solid tumors: novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers. Semin. Cancer Biol. 61, 180–198 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Chabanon, R. M. et al. PBRM1 deficiency confers synthetic lethality to DNA repair inhibitors in cancer. Cancer Res. 81, 2888–2902 (2021). This study provides the first report of a cell-intrinsic induction of the cGAS–STING pathway by ATR inhibitor monotherapy, which operates in the context of synthetic lethality with the SWI/SNF-family protein PBRM1.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Jiang, D. et al. SWI/SNF complex signature as a novel biomarker for immunotherapy in patients with non-small cell lung cancer. Cancer Res. 80 (Suppl. 16), abstract 1323 (2020).

  48. 48.

    Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Liu, X. D. et al. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat. Commun. 11, 2135 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Zhou, H. et al. PBRM1 mutation and preliminary response to immune checkpoint blockade treatment in NSCLC. NPJ Precision Oncol. 4, 6 (2020).

    CAS  Article  Google Scholar 

  51. 51.

    Hakimi, A. A. et al. A pan-cancer analysis of PBAF complex mutations and their association with immunotherapy response. Nat. Commun. 11, 4168 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Hsiehchen, D. et al. DNA repair gene mutations as predictors of immune checkpoint inhibitor response beyond tumor mutation burden. Cell Rep. Med. 1, 100034 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Bartok, E. & Hartmann, G. Immune sensing mechanisms that discriminate self from altered self and foreign nucleic acids. Immunity 53, 54–77 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Ahn, J. et al. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Wang, H. et al. cGAS is essential for the antitumor effect of immune checkpoint blockade. Proc. Natl Acad. Sci. USA 114, 1637–1642 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017). Together with Mackenzie et al. (2017), this article demonstrates that micronuclei accumulated in response to radiotherapy result in cGAS-mediated sensing of cytosolic DNA.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Kitai, Y. et al. DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity. J. Immunol. 198, 1649–1659 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Pantelidou, C. et al. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discov. 9, 722–737 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 (2018). This study is the first to demonstrate, using syngeneic mouse models, that the PARP inhibitor olaparib triggers local and systemic antitumour immunity in BRCA1-deficient contexts via activation of the cGAS–STING pathway.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Chopra, N. et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat. Commun. 11, 2662 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Klarquist, J. et al. STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J. Immunol. 193, 6124–6134 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Erdal, E., Haider, S., Rehwinkel, J., Harris, A. L. & McHugh, P. J. A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1. Genes Dev. 31, 353–369 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    MacKenzie, K. J. et al. CGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Parkes, E. E. et al. Activation of STING-dependent innate immune signaling By S-phase-specific DNA damage in breast cancer. J. Natl Cancer Inst. 109, djw199 (2017). This study demonstrates that DDR-deficient breast cancer cells harbour increased cytosolic DNA, constitutive activation of the cGAS–STING pathway, a resultant type I interferon response and enhanced T cell infiltration and PDL1 expression.

    Article  CAS  Google Scholar 

  69. 69.

    Heijink, A. M. et al. BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. Nat. Commun. 10, 100 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Reisländer, T. et al. BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors. Nat. Commun. 10, 3143 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Bhattacharya, S. et al. RAD51 interconnects between DNA replication, DNA repair and immunity. Nucleic Acids Res. 45, 4590–4605 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Gul, E. et al. Type I IFN–related NETosis in ataxia telangiectasia and Artemis deficiency. J. Allergy Clin. Immunol. 142, 246–257 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Brégnard, C. et al. Upregulated LINE-1 activity in the Fanconi anemia cancer susceptibility syndrome leads to spontaneous pro-inflammatory cytokine production. EBioMedicine 8, 184–194 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Karakasilioti, I. et al. DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria. Cell Metab. 18, 403–415 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Brem, R. & Hall, J. XRCC1 is required for DNA single-strand break repair in human cells. Nucleic Acids Res. 33, 2512–2520 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Zheng, L. et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nat. Med. 13, 812–819 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Quek, H. et al. Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage. J. Leukoc. Biol. 101, 927–947 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Van Oudenhove, E. et al. The cGAS-STING pathway as a driver of the immune-reactive microenvironment in small cell carcinoma of the ovary, hypercalcemic type. Cancer Res. 79 (Suppl. 13), abstract 531 (2019).

  79. 79.

    Wang, L. et al. Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors. J. Clin. Invest. 130, 5951–5966 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Wang, H. et al. Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS). Sci. Rep. 10, 15385 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Ho, S. S. W. et al. The DNA structure-specific endonuclease MUS81 mediates DNA sensor STING-dependent host rejection of prostate cancer cells. Immunity 44, 1177–1189 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Coquel, F. et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature 557, 57–61 (2018). This study identifies a novel and important role of SAMHD1 in the replication stress response which prevents the discharge of ssDNA fragments from stalled replication forks, thereby limiting the activation of the cGAS–STING pathway and its proinflammatory effects.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Kolinjivadi, A. M. et al. Smarcal1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and Stable Rad51 nucleofilaments. Mol. Cell 67, 867–881.e7 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Gratia, M. et al. Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS. J. Exp. Med. 216, 1199–1213 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Yu, Q. et al. DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. Cell Rep. 11, 785–797 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    De Magis, A. et al. DNA damage and genome instability by G-quadruplex ligands are mediated by R loops in human cancer cells. Proc. Natl Acad. Sci. USA 116, 816–825 (2019).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  87. 87.

    Bakhoum, S. F., Kabeche, L., Compton, D. A., Powell, S. N. & Bastians, H. Mitotic DNA damage response: at the crossroads of structural and numerical cancer chromosome instabilities. Trends Cancer 3, 225–234 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018). This study shows that chromosome segregation defects lead to a deleterious tumour cell-autonomous response to cytosolic DNA, which involves the cGAS–STING-dependent activation of non-canonical NF-κB signalling and inflammatory pathways, and promotes metastasis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Chen, Y. A. et al. Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway. Nat. Struct. Mol. Biol. 24, 1124–1131 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Pathare, G. R. et al. Structural mechanism of cGAS inhibition by the nucleosome. Nature 587, 668–672 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Boyer, J. A. et al. Structural basis of nucleosome-dependent cGAS inhibition. Science 370, 450–454 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Liu, H. et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563, 131–136 (2018). This publication describes for the first time unexpected nuclear functions of cGAS, involving its recruitment to DNA DSBs and the suppression of HR activity via interaction with PARP1.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Chen, H. et al. cGAS suppresses genomic instability as a decelerator of replication forks. Sci. Adv. 6, eabb8941 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Raso, M. C. et al. Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage. J. Cell Biol. 219, e202002175 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Canugovi, C. et al. The mitochondrial transcription factor A functions in mitochondrial base excision repair. DNA Repair. 9, 1080–1089 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Chung, K. W. et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab. 30, 784–799.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  101. 101.

    Härtlova, A. et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate. Immun. Immunity 42, 332–343 (2015).

    Article  CAS  Google Scholar 

  102. 102.

    Wolf, C. et al. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat. Commun. 7, 11752 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Kondo, T. et al. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. Proc. Natl Acad. Sci. USA 108, 2969–2974 (2013).

    Article  CAS  Google Scholar 

  105. 105.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Bakhoum, S. F. & Cantley, L. C. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1–27 (2018).

    Article  CAS  Google Scholar 

  107. 107.

    Coquel, F., Neumayer, C., Lin, Y. L. & Pasero, P. SAMHD1 and the innate immune response to cytosolic DNA during DNA replication. Curr. Opin. Immunol. 56, 24–30 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Heidegger, S. et al. RIG-I activation is critical for responsiveness to checkpoint blockade. Sci. Immunol. 4, eaau8943 (2019). This study shows that sensitivity to anti-CTLA4 therapy and its combination with anti-PD1 critically relies on tumour cell-intrinsic activation of the cytosolic RNA sensor RIG1.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Ranoa, D. R. E. et al. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget 7, 26496–26515 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Ghosh, R., Roy, S. & Franco, S. PARP1 depletion induces RIG-I-dependent signaling in human cancer cells. PLoS ONE 13, e0194611 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y. & Sfeir, A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature 591, 477–481 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Koo, C. X. G. E. et al. RNA polymerase III regulates cytosolic RNA:DNA hybrids and intracellular microRNA expression. J. Biol. Chem. 290, 7463–7473 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Mankan, A. K. et al. Cytosolic RNA:DNA hybrids activate the cGAS–STING axis. EMBO J. 33, 2937–2946 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Vanaja, S. K. et al. Bacterial RNA:DNA hybrids are activators of the NLRP3 inflammasome. Proc. Natl Acad. Sci. USA 111, 7765–7770 (2014).

    CAS  Article  Google Scholar 

  118. 118.

    Andriamanampisoa, C. L. et al. BIABooster: online DNA concentration and size profiling with a limit of detection of 10 fg/μL and application to high-sensitivity characterization of circulating cell-free DNA. Anal. Chem. 90, 3766–3774 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Sloan, E. A., Ring, K. L., Willis, B. C., Modesitt, S. C. & Mills, A. M. PD-L1 expression in mismatch repair-deficient endometrial carcinomas, including lynch syndrome-associated and MLH1 promoter hypermethylated tumors. Am. J. Surg. Pathol. 41, 326–333 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Mills, A. M. et al. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am. J. Surg. Pathol. 42, 183–191 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Permata, T. B. M. et al. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene 38, 4452–4466 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Sato, H., Jeggo, P. A. & Shibata, A. Regulation of programmed death-ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine. Cancer Sci. 110, 3415–3423 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Davis, A. A. & Patel, V. G. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7, 278 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Grossman, J. E., Vasudevan, D., Joyce, C. E. & Hildago, M. Is PD-L1 a consistent biomarker for anti-PD-1 therapy? The model of balstilimab in a virally-driven tumor. Oncogene 40, 1393–1395 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Scarpa, M. et al. Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance. Oncotarget 6, 43472–43482 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Haile, S. T. et al. Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J. Immunol. 186, 6822–6829 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Sugiura, D. et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science 364, 558–566 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Zhao, Y. et al. PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity 51, 1059–1073.e9 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Luo, Q. et al. Tumor-derived soluble MICA obstructs the NKG2D pathway to restrain NK cytotoxicity. Aging Dis. 11, 118–128 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Deng, W. et al. Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 348, 136–139 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Aragane, Y. et al. Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J. Cell Biol. 140, 171–182 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Müller, M. et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033–2045 (1998).

    PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Raats, D. A. et al. CD95 ligand induces senescence in mismatch repair-deficient human colon cancer via chronic caspase-mediated induction of DNA damage. Cell Death Dis. 8, e2669 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Upadhyay, R. et al. A critical role for fas-mediated off-target tumor killing in T-cell immunotherapy. Cancer Discov. 11, 599–613 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Ryan, A. E., Shanahan, F., O’Connell, J. & Houston, A. M. Addressing the ‘Fas counterattack’ controversy: blocking fas ligand expression suppresses tumor immune evasion of colon cancer in vivo. Cancer Res. 65, 9817–9823 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Zhu, J. et al. Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes. Nat. Commun. 8, 1404 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Stilmann, M. et al. A nuclear Poly(ADP-Ribose)-dependent signalosome confers DNA damage-induced IκB kinase activation. Mol. Cell 36, 365–378 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Wu, Z. H. et al. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-Mediated IKK activation in response to genotoxic stress. Mol. Cell 40, 75–86 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Hinz, M. et al. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation. Mol. Cell 40, 63–74 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  142. 142.

    Zhang, B. et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat. Commun. 9, 1723 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Murai, J. et al. SLFN11 blocks stressed replication forks independently of ATR. Mol. Cell 69, 371–384.e6 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Mezzadra, R. et al. SLFN11 can sensitize tumor cells towards IFN-γ-mediated T cell killing. PLoS ONE 14, e0212053 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Isnaldi, E. et al. Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer. Breast Cancer Res. Treat. 177, 335–343 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

    O’Donnell, T. et al. Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer. BMC Cancer 18, 87 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Jonna, S. et al. Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC. J. Clin. Oncol. 37, 2627 (2019).

    Article  Google Scholar 

  148. 148.

    Póti, Á. et al. Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts. Br. J. Cancer 119, 1392–1400 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Grimaldi, A. et al. Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens. Commun. Biol. 3, 85 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Klatt, M. G. et al. Epigenetic drug treatment induces presentation of new class of non-exonic, cryptic neoantigens in acute myeloid leukemia cells. Blood 132, 2717 (2018).

    Article  Google Scholar 

  152. 152.

    Bezu, L. et al. Combinatorial strategies for the induction of immunogenic cell death. Front. Immunol. 6, 187 (2015).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Heinhuis, K. M. et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann. Oncol. 30, 219–235 (2019).

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Yamazaki, T., Buqué, A., Ames, T. D. & Galluzzi, L. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. OncoImmunology 9, 1721810 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    D’Amico, L. et al. A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. J. Immunother. Cancer 7, 16 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Pfirschke, C. et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44, 343–354 (2016). This study showed that an appropriately-selected combination of ICD inducers can sensitize immunologically ‘cold’ tumours to PD1 blockade.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).

    CAS  PubMed  Article  Google Scholar 

  158. 158.

    Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Gandhi, L. et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N. Engl. J. Med. 378, 2078–2092 (2018).

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Horn, L. et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N. Engl. J. Med. 379, 2220–2229 (2018).

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Combes, E. et al. Inhibition of ataxia-telangiectasia mutated and Rad3-related (ATR) overcomes oxaliplatin resistance and promotes antitumor immunity in colorectal cancer. Cancer Res. 79, 2933–2946 (2019).

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Dillon, M. T. et al. ATR inhibition potentiates the radiation-induced inflammatory tumor microenvironment. Clin. Cancer Res. 25, 3392–3403 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Yum, S., Li, M., Frankel, A. E. & Chen, Z. J. Roles of the cGAS-STING pathway in cancer immunosurveillance and immunotherapy. Annu. Rev. Cancer Biol. 3, 323–344 (2019).

    Article  Google Scholar 

  165. 165.

    Marcus, A. et al. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49, 754–763.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Schadt, L. et al. Cancer-cell-intrinsic cGAS expression mediates tumor immunogenicity. Cell Rep. 29, 1236–1248.e7 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  167. 167.

    Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017). This study describes that radiation-induced TREX1 expression attenuates tumour cells immunogenicity and reduces CD8+ T cell priming, thereby hampering systemic tumour rejection in the context of combination with ICI.

    PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Liang, H. et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8, 1736 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. 169.

    Hou, Y. et al. Non-canonical NF-κB antagonizes STING sensor-mediated DNA sensing in radiotherapy. Immunity 49, 490–503.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Wang, Z. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci. Rep. 9, 1853 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Nguyen, M., Robillard, L., Lin, K. K., Harding, T. C. & Simmons, A. D. The PARP inhibitor rucaparib activates the STING pathway and enhances antitumor responses of immune checkpoint inhibitors in BRCA deficient syngeneic models. Cancer Res. 78, 1716 (2018).

    Google Scholar 

  172. 172.

    Feng, X. et al. ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways. EMBO J. 39, e104036 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Zhang, Q. et al. Inhibition of ATM increases interferon signaling and sensitizes pancreatic cancer to immune checkpoint blockade therapy. Cancer Res. 79, 3940–3951 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Hu, M. et al. ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage/cGAS-STING activation. J. Clin. Invest. 131, e139333 (2021).

    CAS  PubMed Central  Article  Google Scholar 

  175. 175.

    Kim, C., Wang, X. D. & Yu, Y. Parp1 inhibitors trigger innate immunity via parp1 trapping-induced DNA damage response. eLife 9, e60637 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Polo, S. E. & Almouzni, G. Chromatin dynamics after DNA damage: the legacy of the access-repair-restore model. DNA Repair. 36, 114–121 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Cañadas, I. et al. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat. Med. 24, 1143–1150 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. 178.

    Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563.e19 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Mehdipour, P. et al. Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency. Nature 588, 169–173 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Roulois, D. et al. DNA-demethylating agents target colorectal cancer cell inducing viral mimicry endogenous transcripts. Cell 162, 961–973 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Philippou, Y. et al. Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model. Br. J. Cancer 123, 1089–1100 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Vendetti, F. P. et al. ATR kinase inhibitor AZD6738 potentiates CD8+ T cell-dependent antitumor activity following radiation. J. Clin. Invest. 128, 3926–3940 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Garnett, C. T. et al. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res. 64, 7985–7994 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  186. 186.

    Wei, J. et al. Topotecan enhances immune clearance of gliomas. Cancer Immunol. Immunother. 58, 259–270 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. 187.

    Meng, X. W. et al. Poly(ADP-ribose) polymerase inhibitors sensitize cancer cells to death receptor-mediated apoptosis by enhancing death receptor expression. J. Biol. Chem. 289, 20543–20558 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Ramakrishnan, R. et al. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J. Clin. Invest. 120, 1111–1124 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Sharma, P. et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the checkmate 650 trial. Cancer Cell 38, 489–499.e3 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  190. 190.

    Karzai, F. et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J. Immunother. Cancer 6, 141 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Konstantinopoulos, P. A. et al. Phase II study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer. J. Clin. Oncol. 37, 2786–2794 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  192. 192.

    Färkkilä, A. et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat. Commun. 11, 1459 (2020).

    PubMed Central  Article  CAS  Google Scholar 

  193. 193.

    Teo, M. Y. et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J. Clin. Oncol. 36, 1685–1694 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    Goswami, S. et al. ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC. Sci. Transl. Med. 12, eabc4220 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  195. 195.

    Hanna, G. J. et al. Frameshift events predict anti-PD-1/L1 response in head and neck cancer. JCI Insight 3, e98811 (2018).

    PubMed Central  Article  Google Scholar 

  196. 196.

    Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Dijkstra, K. K. et al. Generation of tumor-reactive T cell co-culture peripheral blood lymph. tumor organoids. Cell 174, 1586–1598.e12 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Jacquelot, N. et al. Predictors of responses to immune checkpoint blockade in advanced melanoma. Nat. Commun. 8, 592 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Dubuisson, A. et al. Immunodynamics of explanted human tumors for immuno-oncology. EMBO Mol. Med. 13, e12850 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  200. 200.

    Mittendorf, E. A. et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396, 1090–1100 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  201. 201.

    Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  202. 202.

    Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  203. 203.

    Domchek, S. M. et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 21, 1155–1164 (2020). This publication presents intermediate results of the first clinical trial evaluating a PARP inhibitor plus anti-PD1/anti-PDL1 combination, which shows promising antitumour activity and a safety profile similar to that of each corresponding monotherapy.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. 204.

    Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Konstantinopoulos, P. A. et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 5, 1141–1149 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Vinayak, S. et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 5, 1132–1140 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Drew, Y. et al. Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC). Ann. Oncol. 31, S615–S616 (2020).

    Article  Google Scholar 

  208. 208.

    Thomas, A. et al. Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase II study. J. Thorac. Oncol. 14, 1447–1457 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    Friedlander, M. et al. Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. Lancet Oncol. 20, 1306–1315 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  210. 210.

    Rodriguez-Moreno, J. F. et al. Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer: NEODURVARIB Trial. J. Clin. Oncol. 38, 542 (2020).

    Article  Google Scholar 

  211. 211.

    Yap, T. A. et al. Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. Eur. J. Cancer 69, S2 (2016).

    Article  Google Scholar 

  212. 212.

    Patel, M. R. et al. Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors. J. Clin. Oncol. 37, 2562 (2019).

    Article  Google Scholar 

  213. 213.

    Keenan, T. E. et al. Clinical efficacy and molecular response correlates of the WEE1 inhibitor adavosertib combined with cisplatin in patients with metastatic triple-negative breast cancer (mTNBC). Clin. Cancer Res. 27, 983–991 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  214. 214.

    Subbiah, V., Solit, D. B., Chan, T. A. & Kurzrock, R. The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥ 10: a decision centered on empowering patients and their physicians. Ann. Oncol. 31, 1115–1118 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  215. 215.

    Prasad, V. & Addeo, A. The FDA approval of pembrolizumab for patients with TMB > 10 mut/Mb: was it a wise decision? No. Ann. Oncol. 31, 1112–1114 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  216. 216.

    McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  217. 217.

    Rousseau, B. et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N. Engl. J. Med. 384, 1168–1170 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Osipov, A. et al. Tumor mutational burden, toxicity, and response of immune checkpoint inhibitors targeting PD(L)1, CTLA-4, and combination: a meta-regression analysis. Clin. Cancer Res. 26, 4842–4851 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. 220.

    Touat, M. et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580, 517–523 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Campbell, M. R., Wang, Y., Andrew, S. E. & Liu, Y. Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect. Oncogene 25, 2531–2536 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  222. 222.

    Jiricny, J. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 7, 335–346 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  223. 223.

    Sivick, K. E. et al. Magnitude of therapeutic STING activation determines CD8+ T cell-mediated anti-tumor immunity. Cell Rep. 25, 3074–3085.e5 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  224. 224.

    Luo, M. et al. Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer. Signal. Transduct. Target. Ther. 5, 141 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  225. 225.

    Lu, C.-S. et al. Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy. J. Immunother. Cancer 8, e001392 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  226. 226.

    Tran, L. et al. Cisplatin alters antitumor immunity and synergizes with PD-1/PD-L1 inhibition in head and neck squamous cell carcinoma. Cancer Immunol. Res. 5, 1141–1151 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  227. 227.

    Zhang, M. et al. 5-FU-induced upregulation of exosomal PD-L1 causes immunosuppression in advanced gastric cancer patients. Front. Oncol. 10, 492 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  228. 228.

    Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  229. 229.

    Yin, Z. et al. Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1. J Immunother Cancer 9, e001698 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  230. 230.

    Oaknin, A. et al. Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol. 6, 1–7 (2020).

    PubMed Central  Article  Google Scholar 

  231. 231.

    Parkhurst, M. R. et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov. 9, 1022–1035 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  232. 232.

    Saini, S. K., Rekers, N. & Hadrup, S. R. Novel tools to assist neoepitope targeting in personalized cancer immunotherapy. Ann. Oncol. 28, xii3–xii10 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  233. 233.

    Wells, D. K. et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 183, 818–834.e13 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  234. 234.

    Bassani-Sternberg, M. Mass spectrometry based immunopeptidomics for the discovery of cancer neoantigens. Methods Mol. Biol. 1719, 209–221 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  235. 235.

    Hadrup, S. R. et al. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat. Methods 6, 520–526 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  236. 236.

    Slota, M., Lim, J. B., Dang, Y. & Disis, M. L. ELISpot for measuring human immune responses to vaccines. Expert Rev. Vaccines 10, 299–306 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. 237.

    van Vloten, J. P. et al. Quantifying antigen-specific T cell responses when using antigen-agnostic immunotherapies. Mol. Ther. Methods Clin. Dev. 13, 154–166 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  238. 238.

    Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  239. 239.

    Kadigamuwa, C. et al. Role of retinoic acid receptor-γ in DNA damage-induced necroptosis. iScience 17, 74–86 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  240. 240.

    Smith, H. G. et al. RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma. EMBO Mol. Med. 12, e10979 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  241. 241.

    Jennings, V. A. et al. Potentiating oncolytic virus-induced immune-mediated tumor cell killing using histone deacetylase inhibition. Mol. Ther. 27, 1139–1152 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  242. 242.

    Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  243. 243.

    Shifrut, E. et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 175, 1958–1971.e15 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. 244.

    Gee, S. et al. Developing an arrayed CRISPR-Cas9 Co-Culture screen for immuno-oncology target ID. SLAS Discov. 25, 581–590 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245.

    Zhang, J., Späth, S. S. & Katz, S. G. Genome-Wide CRISPRi/a screening in an in vitro coculture assay of human immune cells with tumor cells. Methods Mol. Biol. 2097, 231–252 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  246. 246.

    Freeman, A. J. et al. Natural killer cells suppress T cell-associated tumor immune evasion. Cell Rep. 28, 2784–2794.e5 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Y. L. Lin and H. Técher for their careful reading of the manuscript and insightful comments. The work in the laboratory of S.P.-V. is supported by programme grants from ATIP-Avenir INSERM / La Ligue Nationale Contre le Cancer, SIRIC SOCRATE-2 (INCa-DGOS-INSERM_12551), Cancéropôle Ile-de-France (2017-1-EMERG-72) and Association pour la Recherche contre le Cancer (ARC PGA1 RF 20190208576). R.M.C. received funding from Fondation Bettencourt-Schueller, Fondation des Treilles, Fondation Philanthropia-Lombard Odier, Institut Servier, and Cancéropôle Ile-De-France.

Author information

Affiliations

Authors

Contributions

R.M.C. and M.R. researched data for the article. R.M.C., M.R. and S.P.-V. contributed substantially to discussion of the content. R.M.C., M.R. and S.P.-V. wrote the article. All authors contributed to reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Sophie Postel-Vinay.

Ethics declarations

Competing interests

R.M.C., M.R. and P.P. have no conflicts of interest or financial interests to disclose. C.J.L. is a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventor scheme. C.J.L. has received research funding from AstraZeneca, Merck KGaA, Artios and Pfizer, has received consultancy and/or advisory fees from Astra Zeneca, Merck KGaA, Artios, Tango and GLG, and is a shareholder of OviBio and Tango. J.-C.S. has received consultancy fees from Relay Therapeutics, is a shareholder of AstraZeneca, Gritstone and Daiichi Sankyo, and is a member of the Hookipa board of directors. S.P.-V. has received research funding from Merck KGaA, Boehringer Ingelheim and Roche for unrelated research projects. As part of the Drug Development Department (DITEP), S.P.-V. is a principal investigator or a subinvestigator on clinical trials by Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare AG, Bbb Technologies BV, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech Inc., Glaxosmithkline, H3 Biomedicine Inc., Hoffmann La Roche AG, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharmaceutical Development Inc., Loxo Oncology, Lytix Biopharma AS, Medimmune, Menarini Ricerche, Merck Sharp & Dohme-Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc. and Xencor. S.P.-V. has participated in advisory boards for Merck KGaA.

Additional information

Peer review information

Nature Reviews Cancer thanks L.A. Byers, who co-reviewed with C. Gay; G.M. Li, who co-reviewed with Y. Huang; and E. Parkes for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Genomic instability

Considered as a hallmark of cancer, a direct consequence of DNA damage response and DNA replication deficiencies, which promote mutagenesis and tumour progression.

Tumour cell-autonomous responses

Set of intrinsic cellular processes that occur within a tumour cell independently of the presence or interaction with other cells.

Mismatch repair

(MMR). DNA damage response pathway that corrects mismatched nucleotides in otherwise complementary paired DNA strands.

Adjuvanticity

The capacity of a cell to produce immunogenic adjuvants; that is, endogenous (usually non-specific) molecules that stimulate, activate, potentiate or modulate the antitumour immune response at either the cellular level or the humoral level.

Mutational signatures

Combinations of mutations that arise from and are characteristic of specific endogenous or exogenous mutagenic processes, such as mutagenesis secondary to DNA damage response or chromatin remodelling defects, or exposure to DNA-damaging agents.

Tumour neoantigens

Tumour-specific antigens that derive from non-synonymous somatic mutations exclusively present in a tumour.

Tumour mutational burden

(TMB). The total number of mutations carried by a tumour at a given time, classically determined by whole-genome sequencing or whole-exome sequencing.

Homologous recombination

(HR). DNA damage response pathway that mediates high-fidelity repair of DNA lesions, notably double-strand breaks, using a sister chromatid as a template during the S and G2 phases of the cell cycle.

Base-excision repair

DNA damage response pathway that removes single-base lesions caused by alkylating agents or reactive oxygen species.

Nucleotide-excision repair

DNA damage response pathway that removes large DNA adducts (such as those caused by exposure to UV light) or base modifications that results in distortion of the DNA double helix using the opposite strand as a template for repair.

Chromatin remodelling complexes

ATP-dependent protein complexes that modify the chromatin structure to regulate gene expression and facilitate DNA repair.

Replication stress response

Series of molecular events that occur when a cell is subjected to replication stress, which corresponds to the non-physiological and persistent slowing down or stalling of replication forks — often caused by lesions in the DNA undergoing replication.

cGAS–STING pathway

Cytosolic DNA-sensing pathway that functions to detect pathogen-derived or damage-derived DNA fragments in the cytosol, and consequently triggers a cell-autonomous innate immune response.

Pattern recognition receptors

Innate immune receptors capable of recognizing pathogen-associated molecular patterns or host-derived damage-associated molecular patterns.

Inflammasome

Multiprotein cytosolic complex that mediates the activation of a caspase 1-dependent proinflammatory response characterized by the production of IL-1β and IL-18.

Immunogenic cell death

(ICD). Peculiar form of cell death characterized by the production of damage-associated molecular patterns that elicit an immunostimulatory response.

Micronuclei

Cytosolic nuclear structures formed outside the primary nucleus, consisting of nucleus-derived DNA isolated from the rest of the cytosol by a nuclear envelope.

Type I interferon

Class of secreted proteins involved in the activation of cell-autonomous innate immune pathways that stimulate natural killer cell and T cell function.

Non-homologous end joining

Error-prone DNA damage response pathway that mediates repair of DNA double-strand breaks by rejoining DNA ends without reliance on a homologous template.

Interstrand crosslink repair

DNA damage response pathway involved in the processing of interstrand crosslinks, those DNA lesions caused by platinum-based chemotherapies that block DNA replication and/or transcription due to the formation of a covalent bond between DNA bases on opposite strands of DNA.

Damage-associated molecular patterns

Stimuli produced as a result of cellular stress in dying or damaged cells, which often triggers an immunostimulatory response through the activation of various pattern recognition receptors.

Chromosomal instability

(CIN). Phenotype referring to a higher than normal rate of chromosome mis-segregation during mitosis, which often results in structural abnormalities (for example, deletions, inversions or translocations), and numerical abnormalities (for example, copy number alterations or aneuploidy).

Alternative lengthening of telomeres

A recombination-based mechanism that allows telomere length maintenance in the absence of telomerase activity.

Senescence-associated secretory phenotype

(SASP). Phenotype of senescent cells characterized by the secretion of a variety of cytokines, chemokines and other soluble factors that promote inflammation.

Abscopal responses

Therapeutic responses induced by radiotherapy when irradiation of tumour cells at the primary tumour site produces a systemic response and biologically relevant changes in distant metastatic sites, which may or may not have been irradiated themselves.

Synthetic lethality

Concept illustrating the cell death that results from combined inactivation or inhibition of two genes or gene products that are non-lethal when inactivated individually.

Window-of-opportunity

Clinical trial in which treatment-naive patients receive one or more investigational cancer treatments between their cancer diagnosis and standard treatment (essentially surgery), allowing the collection of tumour biopsy samples before and after treatment.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chabanon, R.M., Rouanne, M., Lord, C.J. et al. Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat Rev Cancer 21, 701–717 (2021). https://doi.org/10.1038/s41568-021-00386-6

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing