STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer

• DOI: 10.1038/s41467-022-30568-1
• Publication Date: 2022-05-31T10:03:42Z
• Authors: Qiwei Wang; Johann S. Bergholz; Liya Ding; Ziying Lin; Sheheryar K. Kabraji; Melissa E. Hughes; Xiadi He; Shaozhen Xie; Tao Jiang; Weihua Wang; Jason J. Zoeller; Hye-Jung Kim; Thomas M. Roberts; Panagiotis A. Kon...; Ursula A. Matulonis; Deborah A. Dillon; Eric P. Winer; Nancy U. Lin; Jean J. Zhao
• Keywords: Sting

PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, impact this class in patients BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both vivo and vitro. Mechanistically, BRCA1-deficient cells induce pro-tumor polarization TAMs, which turn suppress PARPi-elicited DNA damage cells, leading to reduced production dsDNA fragments synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like into an M1-like state macrophage manner. Systemic administration agonist breaches multiple layers cell-mediated suppression immune synergizes growth. The therapeutic benefits combination require host are mediated type I IFN response CD8