Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-defi cient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8 + T-cell infi ltration and activation in vivo , and that CD8 + T-cell depletion severely compromises antitumor effi cacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-defi cient compared with HR-profi cient TNBC cells and in vivo models. CRISPR-mediated knockout of STING in cancer cells prevents proinfl ammatory signaling and is suffi cient to abolish olaparib-induced T-cell infi ltration in vivo. These fi ndings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8 + T-cell recruitment and antitumor effi cacy. The data provide insight into the mechanism of action of PARP inhibitors in BRCA-associated breast cancer.

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