STXBP6-driven signaling cascade alters lipid peroxidation in tumor-associated macrophages to facilitate ovarian cancer progression.

Ovarian cancer (OC) is highly lethal, with late diagnosis and frequent treatment resistance. Tumor-associated macrophage (TAM) are key immunosuppressive cells whose metabolic state critically influences redox homeostasis and immune function in the tumor microenvironment (TME). Here, we show that STXBP6 expression is elevated in OC TAMs. Mechanistically, STXBP6 promotes cPLA2-mediated arachidonic acid release and PKCβ-dependent nuclear translocation and activation of arachidonate 5-lipoxygenase (ALOX5), driving alterations in arachidonic acid metabolism and downstream 5-HETE production. Lipidomics, transcriptomics, and functional assays demonstrated that STXBP6 regulates lipid droplet formation, lipid peroxidation, and TAM polarization, linking redox-regulated lipid metabolism to immunosuppressive phenotypes. Using in vitro TAM models and in vivo OC models, including TAMs-OC co-implantation, we further confirmed that the STXBP6/cPLA2/ALOX5/5-HETE axis enhances tumor growth, metastasis, and the establishment of an immunosuppressive microenvironment. These findings reveal a previously unrecognized mechanism by which STXBP6 drives TAM metabolic reprogramming and immune modulation in OC, highlighting STXBP6 as a potential target for immunometabolic therapy.