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by claude@2026-07, 2026-07-03
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The study investigated how focal adhesion kinase (FAK) inhibition affects immune cell recruitment and immunotherapy response in syngeneic high-grade serous ovarian cancer models, using ifebemtinib or tumor-specific FAK knockout and assessing peritoneal macrophage and B cell behavior. FAK inhibition increased resident peritoneal macrophage CXCL13 expression via a macrophage GATA6-dependent mechanism and promoted B cell infiltration, while macrophage GATA6 inactivation blocked CXCL13 and increased tumor growth; the authors further found that omega-3 fatty acid–enriched exosomes from FAK-deficient or ifebemtinib-treated tumors stimulated CXCL13 production and macrophage reprogramming, including in human HGSOC-associated macrophages. Combining ifebemtinib with pegylated doxorubicin and anti-TIGIT extended survival and was associated with tertiary lymphoid structure formation. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
SUMMARY 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. eTOC Blurb High-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation. Bullet points Genetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration Tumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13 FAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures Omega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13
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SUMMARY
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.
eTOC Blurb High-grade serous ovarian cancer remains difficult to treat due to therapy resistance. Chen et. al. reveal that tumor FAK inhibition educates macrophages to express CXCL13 associated with B cell infiltration - highlighting a new therapeutic pathway linking FAK inhibition, omega-3 fatty acid containing exosomes, and macrophage mediated anti-tumor activation.
Bullet points
Genetic or small molecule FAK inhibition enhances ovarian tumor B cell infiltration
Tumor FAK inhibition stimulates GATA6+ macrophages to make CXCL13
FAKi, pegylated doxorubicin and anti-TIGIT promote tertiary lymphoid structures
Omega-3 fatty acids stimulate human HGSOC ascites macrophages to make CXCL13
Competing Interest Statement
D. Stupack is a consultant for Amplia Therapeutics Limited. All other authors declare that they have no conflicts of interest.
Footnotes
↵* University of Turku, Department of Life Technologies, Finland
Declaration of Interests
D. Stupack is a consultant for Amplia Therapeutics Limited. All other authors declare that they have no conflicts of interest.
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