Obesity-driven extracellular vesicle signaling in cancer: mechanistic insights and clinical implications

Abstract Obesity is a rapidly escalating global health challenge and a major, modifiable driver of cancer risk and poor outcomes across at least 13 malignancies, including endometrial, colorectal, breast, pancreatic, hepatic, renal, ovarian, and esophageal adenocarcinoma. Beyond endocrine and metabolic effects, obesity establishes a tumor-permissive systemic state characterized by adipose hypoxia, chronic inflammation, insulin resistance, and adipokine imbalance. Here, we synthesize evidence that extracellular vesicles (EVs) serve as a central mechanistic conduit through which these obesity-associated stress programs are transmitted to tumor and stromal compartments, driving cancer initiation, progression, immune evasion, metastasis, and therapy resistance. Obesity amplifies EV biogenesis and reprograms EV cargo through hypoxia- and inflammation-responsive signaling and altered endosomal trafficking, enriching EVs with coordinated lipid, RNA, and protein modules that durably rewire recipient cells. Functionally, obesity-conditioned EVs reinforce oncogenic growth and survival signaling, promote epithelial plasticity and angiogenesis, remodel the tumor microenvironment toward immune suppression and extracellular matrix reorganization, and facilitate pre-metastatic niche formation. Clinically, EVs provide a stable, information-rich substrate for liquid biopsy development, with emerging EV signatures showing promise for early detection, risk stratification, and longitudinal disease monitoring in obesity-associated cancers. We conclude by outlining key mechanistic, technological, and translational priorities required to advance EV-based biomarkers and to therapeutically disrupt obesity-driven intercellular communication.