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Updated: Jan 16, 2026
Author Spotlight: Advanced Ex Vivo Model for Investigating Cancer-Adipose Microenvironment Interaction
Published on: January 26, 2024
Ovarian Tumor FAK Inhibition Releases Omega-3 Fatty Acids Stimulating GATA6 Peritoneal Macrophage CXCL13 Production
Xiao Lei Chen1, Kevin M Tharp2, Marjaana Ojalill1
1University of California San Diego, Department of Obstetrics, Gynecology, and Reproductive Sciences, Moores Cancer Center, Division of Gynecologic Oncology, La Jolla, CA.
Abstract:
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the USA due to chemo- and immuno-therapy resistance. We show that focal adhesion kinase (FAK) inhibition with ifebemtinib or tumor genetic FAK knockout (KO) in syngeneic ovarian tumor models stimulated resident large peritoneal macrophages to express CXCL13 chemokine and promoted B cell infiltration. Macrophage GATA6 inactivation prevented CXCL13 expression and enhanced FAK-KO tumor growth. Combining ifebemtinib with pegylated doxorubicin chemotherapy and anti-TIGIT immune checkpoint antibody extended survival with tumor-associated tertiary lymphoid structure formation. Mechanistically, FAK-KO heat-treated conditioned media contained exosomes enriched with omega-3 fatty acids which stimulated macrophage CXCL13 production. Ifebemtinib-treated tumors, FAK-KO exosomes, and purified eicosapentaenoic acid enhanced murine and human HGSOC-associated tumor macrophage reprogramming and CXCL13 expression. Overall, our studies define a tumor to macrophage signaling linkage via omega-3 exosome lipids supporting B cell recruitment, survival, immunotherapy enhancement, and actionable via small molecule FAK inhibition.
Insights
Focal adhesion kinase (FAK) inhibition in ovarian cancer prompts macrophages to attract B cells, enhancing immunotherapy. Omega-3 fatty acids in exosomes mediate this crucial tumor-to-macrophage communication, improving treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- High-grade serous ovarian cancer (HGSOC) presents significant therapeutic challenges due to resistance to conventional treatments.
- Identifying novel pathways to overcome chemo- and immuno-therapy resistance is critical for improving patient survival.
Purpose of the Study:
- To investigate the role of focal adhesion kinase (FAK) in modulating the tumor microenvironment in HGSOC.
- To explore the potential of FAK inhibition to enhance anti-tumor immunity and therapeutic responses.
Main Methods:
- Utilized syngeneic ovarian tumor models with FAK inhibition (ifebemtinib) or genetic knockout (KO).
- Analyzed macrophage phenotype, chemokine expression (CXCL13), and B cell infiltration.
- Investigated the role of exosomes and omega-3 fatty acids in tumor-macrophage signaling.
- Combined FAK inhibition with chemotherapy and immune checkpoint blockade in therapeutic studies.
Main Results:
- FAK inhibition or KO in HGSOC models induced CXCL13 expression in macrophages, promoting B cell infiltration.
- Macrophage GATA6 inactivation abrogated CXCL13 induction and accelerated tumor growth.
- Combination therapy (ifebemtinib, chemotherapy, anti-TIGIT) significantly extended survival and increased tertiary lymphoid structures.
- Exosomes from FAK-inhibited/knockout tumors, enriched with omega-3 fatty acids, reprogrammed macrophages to express CXCL13.
Conclusions:
- FAK inhibition establishes a tumor-macrophage signaling axis via omega-3 fatty acid-enriched exosomes.
- This pathway enhances B cell recruitment and supports immunotherapy efficacy in HGSOC.
- Targeting FAK represents a promising strategy to overcome treatment resistance in ovarian cancer.
