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

Abstract 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.