2026-03-05 カリフォルニア大学サンディエゴ校 (UCSD)
These microscopy images show tertiary lymphoid structures, immune cell hubs associated with improved patient survival and stronger responses to immunotherapy. Inhibiting FAK encourages the formation of these hubs. Red represents B cells, yellow represents T cells, and all cells are marked in blue. Courtesy of UC San Diego Health Sciences
＜関連情報＞
- https://today.ucsd.edu/story/rewiring-immune-system-offers-new-path-to-better-ovarian-cancer-treatment
- https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00087-2
FAK inhibition in ovarian cancer releases omega-3 fatty acids to program CXCL13-producing anti-tumor resident peritoneal macrophages
Xiao Lei Chen ∙ Kevin M. Tharp ∙ Marjaana Ojalill ∙ … ∙ Kathleen M. Fisch ∙ Dwayne G. Stupack ∙ David D. Schlaepfer
Cell Reports Published:February 24, 2026
DOI:https://doi.org/10.1016/j.celrep.2026.117009
Highlights
- FAKi, pegylated doxorubicin, and anti-TIGIT enhance survival and tertiary lymphoid formation
- Tumor FAK inhibition released omega-3 fatty acid exosomes, enhancing macrophage CXCL13
- Macrophage GATA6 loss enhanced FAK-knockout tumor growth and reduced peritoneal B cells
- Omega-3 fatty acids stimulate human ovarian tumor-associated macrophage CXCL13
Summary
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.
