Polyunsaturated Fatty Acids Promote Protumoral Macrophage Polarization via a RhoA-YAP1 Signaling Pathway in the Ovarian Cancer Microenvironment

Abstract Tumor-associated macrophages (TAMs) are crucially associated with tumor development and progression; however, it remains unclear how the tumor microenvironment (TME) rewires the metabolic circuits and preferentially induces TAMs to polarize toward a protumoral phenotype. Here, we report that polyunsaturated fatty acids (PUFAs) in malignant ascites promote protumoral M2-like TAMs deposition and facilitate peritoneal metastases of epithelial ovarian cancer (EOC). We demonstrated that PUFAs in the lipid-enriched malignant ascites inactivate RhoA, reducing nuclear YAP1 in macrophages and promoting protumoral M2-like TAMs polarization with OXPHOS metabolism. Conditional Yap1 depletion in murine MΦs leads to skew macrophage polarization toward protumoral M2-like TAMs that, in turn, suppress CD8+ T cell infiltration and aggravate tumor colonization in vivo. Noticeably, the significance of nuclear YAP1 depletion was evinced in the infiltrating TAMs in tumor spheroids of malignant ascites from EOC patients. In contrast, restored nuclear YAP1 expression in TAMs by pharmacological suppression of MST1/2 enhances tumoricidal M1-like TAMs population and CD8+ T cells infiltration, restricting EOC peritoneal metastasis. These results indicate that PUFAs are a key player in promoting tumor-infiltrated TAMs polarization that, in turn, facilitates EOC tumor growth and metastasis.