Abstract Although PARP inhibitors are approved for breast cancer patients with germline mutations in BRCA1/2, usage fails to extend overall survival or promote the efficacy of immunotherapy, despite preclinical evidence that PARP inhibitors promote T cell-mediated immunity through activation of the cGAS-STING pathway. Here we show that tumor ectonucleotidase ENPP1, through its ability to degrade extracellular 2’3’-cGAMP, is a potent suppressor of T cell infiltration and effector function in preclinical models of Brca1-deficient disease. Deletion or therapeutic targeting of ENPP1 with a novel blocking nanobody improved tumor control and unleashed the combinatorial efficacy of PARP inhibitors and anti-PD1 immunotherapy. Both tumor and host STING were required for tumor control, with macrophage STING signaling reducing their suppressive capacity and tumor STING promoting antigen presentation. ENPP1 expression negatively correlates with overall survival and response to PARP inhibition in patients with homologous repair deficiency, in addition to regulating the efficacy of chemoimmunotherapy, highlighting its therapeutic potential. Citation Format: Jie Li, Charlotte Mason, Kay Hänggi, Achintyan Gangadharan, Xing Qingyu, Olabisi Osunmakinde, Xiaoxian Liu, Daiana Celias, Alyssa Obermayer, Tao Li, Conor C. Lynch, Timothy I. Shaw, Justin M. Lopchuk, Xiaoqing Yu, Vincent C. Luca, Brian Ruffell. Homologous recombination deficiency sensitizes breast cancer to therapeutic targeting of the ectonucleotidase ENPP1 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB402.
Li et al. (Fri,) studied this question.