FAK inhibition in ovarian cancer releases omega-3 fatty acids to program CXCL13-producing anti-tumor resident peritoneal macrophages
High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by therapy resistance. Focal adhesion kinase (FAK) is highly expressed in HGSOC, yet its impact on tumor-immune communication remains incompletely defined. Using three syngeneic ovarian cancer models, we show that FAK inhibition (FAKi) increased macrophage CXCL13 expression and promoted peritoneal B cell infiltration. Combining FAKi with low-dose pegylated doxorubicin and anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint blockade suppressed orthotopic ovarian tumor growth, extended survival, and induced tertiary lymphoid structures. Macrophage lineage factor GATA6 inactivation reduced CXCL13 expression, enhanced FAK-knockout tumor growth, and limited ascites B cell accumulation. Mechanistically, FAKi-treated or FAK-deficient tumor cells release exosomes enriched in omega-3 fatty acids that stimulated macrophage CXCL13 production. Exposure of macrophages to tumor-derived omega-3 lipids or eicosapentaenoic acid induced anti-tumor reprogramming and CXCL13 expression. Together, these findings reveal a tumor lipid-macrophage signaling axis activated by FAKi that supports B cell recruitment and anti-TIGIT immunotherapy.
Authors
- Shizhen Emily Wang (ORCID: https://orcid.org/0000-0002-5036-8175)
- Xiao Lei Chen (ORCID: https://orcid.org/0000-0001-7998-9963)
- Denise C. Connolly (ORCID: https://orcid.org/0000-0003-0888-2004)
- Patrick Peñalosa
- Travis G. Nemkov (ORCID: https://orcid.org/0000-0001-8566-7119)
- Terrance James Haanen (ORCID: https://orcid.org/0000-0003-1461-3169)
- Antonia Boyer
- Kevin M. Tharp (ORCID: https://orcid.org/0000-0002-3543-3266)
- Kathleen M. Fisch (ORCID: https://orcid.org/0000-0002-0117-7444)
- Marjaana Ojalill (ORCID: https://orcid.org/0000-0003-3181-6742)
- Ramez N. Eskander (ORCID: https://orcid.org/0000-0002-2101-1935)
- James Lee (ORCID: https://orcid.org/0000-0003-3079-5484)
- Duygu Ozmadenci (ORCID: https://orcid.org/0000-0002-5463-7766)
- David D. Schlaepfer (ORCID: https://orcid.org/0000-0003-4814-9210)
- Elise Tahon
- Safir Ullah Khan (ORCID: https://orcid.org/0000-0002-1285-8907)
- Cray Minor
- Christine Lawson
- Marvin Xia
- Dwayne G. Stupack
- Michael T. McHale
- Elias Warren
- Colin C. Anderson
- Michael Rose
- Alfredo A. Molinolo
- Yichi Zhang
- Monica V. Estrada
Institutions
- Fox Chase Cancer Center (US)
- Discovery Institute (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-02-24
- DOI
- https://doi.org/10.1016/j.celrep.2026.117009
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00