Faculty Collaboration Database

eIF4E Enriched Extracellular Vesicles Induce Immunosuppressive Macrophages through HMGCR-Mediated Metabolic Rewiring. Adv Sci (Weinh) 2025 Nov;12(42):e06307

Date

08/18/2025

Pubmed ID

40820860

Pubmed Central ID

PMC12622447

DOI

10.1002/advs.202506307

Scopus ID

2-s2.0-105013566484 (requires institutional sign-in at Scopus site)   5 Citations

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.

Author List

Mittal S, Nenwani M, Pulikkal Kadamberi I, Kumar S, Animasahun O, George J, Tsaih SW, Gupta P, Singh M, Geethadevi A, Dey C, Meurs N, Shankaran A, Chaluvally Raghavan P, Nagrath D, Pradeep S

Authors

Pradeep Chaluvally-Raghavan PhD Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Anjali Geethadevi Research Scientist I in the Obstetrics and Gynecology department at Medical College of Wisconsin
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Mona Roshan Singh Postdoctoral Researcher 4 in the Obstetrics and Gynecology department at Medical College of Wisconsin
Shirng-Wern Tsaih Research Scientist II in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line, Tumor
Eukaryotic Initiation Factor-4E
Extracellular Vesicles
Female
Humans
Hydroxymethylglutaryl CoA Reductases
Macrophages
Mice
Ovarian Neoplasms
Tumor Microenvironment