Normalized values were then mapped back to natural values for calculation. this paper. Abstract PARP inhibitors (PARPi) have drastically changed the treatment scenery of advanced ovarian tumors with mutations. However, the impact of this class of inhibitors in patients with advanced deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, BCIP but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast malignancy. and pathogenic variants10,11, highlighting the need to understand the mechanisms of PARPi resistance in advanced breast cancers in the effort to develop strategies to improve responses to PARPi. Our understanding of the mechanisms underlying the therapeutic efficacy of PARPi is still evolving. Since first described in 200512,13, PARPi have been BCIP shown to exert synthetic lethality in HR-deficient tumor cells via multiple mechanisms, including inhibiting base excision repair (BER), trapping of PARPCDNA KRT4 complexes, activating error-prone non-homologous end joining (NHEJ), and interfering with PARP1/POLQ-mediated option end joining (alt-EJ)14,15. Recently, we as well as others demonstrated that this immune response brought on by PARPi is also required for tumor elimination in vivo16C18. Using a genetically designed mouse model (GEMM) of and (referred as BP), as protein-truncating mutations are frequently found in and (mice with or without intraductal injection of Ad-Cre (test or MannCWhitney test (d), (f),?and (g). ns not significant. Source data are provided as a Source Data file. Notably, primary tumor cells derived from BP tumors can be cultured in vitro as well as allografted back into the mammary excess fat pads of syngeneic FVB/N mice, allowing detailed studies of tumor cell-intrinsic activities, as well as their interactions with the host immune system and their responses to therapeutic interventions. We first assessed BP cell-intrinsic response to PARP inhibition in vitro. BP cells with reconstituted wild-type (WT) BRCA1 (BP?+?BRCA1) were used as a control. We found that olaparib treatment had little effect on BP?+?BRCA1 cells, but significantly inhibited clonogenic growth of BP cells in a dose-dependent manner (Supplementary Fig.?1eCg). Despite the sensitivity to olaparib in vitro, when orthotopic BP tumor-bearing FVB mice were treated with olaparib, tumors exhibited an initial slower growth than control tumors but nevertheless progressed through treatment and presented growth rates comparable to control BCIP BCIP tumors at later time points (Fig.?1c). While there was a statistically significant reduction in tumor size compared to control tumors, the effect of olaparib on and and overexpression of cMyc (referred as PBM), where we found that the ovarian tumors had a dramatic response to olaparib with a strong activation of anti-tumor CD8+ T cell response in the TIME, which was essential for the BCIP therapeutic efficacy of PARPi16. BRCA1-deficient breast tumor-associated macrophages mediate immune suppression To better understand the TIME of BP tumors, we performed tissue-based multiplexed cyclic immunofluorescence (CyCIF) analysis. We found that BP tumors are highly infiltrated by CD45+ immune cells, of which myeloid cells (CD11b+, F4/80+ or CD11c+), such as F4/80+ macrophages, are more abundant than T lymphocytes (CD4+ or CD8+) (Supplementary Fig.?1h). We then assessed the TIME of BP tumors following PARPi treatment. Analysis of TILs revealed that CD8+ T cells and effector CD8+ T.