Highlights d CD8 + T cell infiltration in tumors is associated with CCL5 and CXCL9 coexpression d CCL5 is expressed in tumor cells and CXCL9 is induced in APCs in response to IFN-g d CCL5 hi CXCL9 hi tumors are immunoreactive and respond to checkpoint blockade d Cancer cells negatively regulate CCL5 expression by epigenetic silencing mechanisms

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SUMMARY In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1 -mutated ( BRCA1 mut ) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 + T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53 −/− Brca1 −/− but not Brca1 +/+ ovarian tumors in vivo , offering rational combinatorial therapies for HRD cancers.