Abstract 7951: Ovarian tumor FAK inhibition releases omega-3 fatty acids stimulating GATA6 peritoneal macrophage CXCL13 production augmenting TIGIT immunotherapy

Abstract High grade serous ovarian cancer (HGSOC) is a lethal gynecologic malignancy due to accumulated therapy resistance. Focal adhesion kinase (FAK) expression is elevated in HGSOC, and inhibition of FAK activity (FAKi) in syngeneic ovarian tumors reduced tumor burden with elevated CXCL13 chemokine expression by peritoneal macrophages. Combining FAKi with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody repressed tumors and extended survival with tertiary lymphoid structure formation. Peritoneal macrophage GATA6 inactivation reduced CXCL13 expression in vivo, enhanced FAK knockout (KO) tumor growth, and limited ascites B cell infiltration. FAKi-treated or FAK-KO conditioned media contained exosomes enriched with omega-3 fatty acids that stimulated macrophage CXCL13 production. As isolated by paracentesis, FAKi-treated HGSOC tumor cells or purified macrophages treated with eicosapentaenoic acid triggered anti-tumor macrophage reprogramming and CXCL13 expression. Together, our studies define a tumor lipid to macrophage signaling linkage upon FAK inhibition supporting B cell recruitment, survival, and anti-TIGIT immunotherapy enhancement. Citation Format: Xiao Lei Chen, Kevin M. Tharp, Marjaana Ojalill, Duygu Ozmadenci, Antonia Boyer, Terrance J. Hannen, Christine Lawson, Hyojae J. Lee, Marvin Xia, Elise Tahon, Yichi Zhang, Cray Minor, Safir U. Khan, Colin C. Anderson, Travis Nemkov, Michael Rose, Monica V. Estrada, Alfredo A. Molinolo, Elias Warren, Patrick Penalosa, Ramez N. Eskander, Michael T. McHale, Shizhen E. Wang, Denise C. Connolly, Kathleen M. Fisch, Dwayne G. Stupack, David D. Schlaepfer. Ovarian tumor FAK inhibition releases omega-3 fatty acids stimulating GATA6 peritoneal macrophage CXCL13 production augmenting TIGIT immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7951.