eIF4E Enriched Extracellular Vesicles Induce Immunosuppressive Macrophages through HMGCR‐Mediated Metabolic Rewiring

Tumor driven immune suppression poses a significant impediment to the success of immunotherapy in ovarian cancer. Among the various mechanisms contributing to immune suppression, intracellular communication facilitated by tumor-derived extracellular vesicles (EVs) within the tumor microenvironment emerges as a pivotal factor influencing tumor growth. Here, it is demonstrated that extracellular vesicle-packaged eIF4E from tumor cells alters protein translation in macrophages, contributing to antitumor immune response. Mechanistically, tumor derived EV-packaged eIF4E significantly enhances the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), driving the synthesis and secretion of cholesterol. This, in turn, activates macrophages and causes immunosuppression through the X-box binding protein 1 and Programmed death-ligand 1 (XBP1/PD-L1) axis. Strikingly, both genetic and pharmacological depletion of HMGCR in macrophages effectively restores their antitumor activity. Clinically, elevated HMGCR expression in tumor-associated macrophages is associated with poor survival outcomes in ovarian cancer patients. The pivotal role of eIF4E is underscored here as a key signaling mediator, facilitating the communication between tumor and immune cells via EVs to promote immune suppression and suggesting HMGCR as a potential therapeutic target for tumor immunotherapy.