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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.<\/jats:p>","DOI":"10.1038\/s41389-026-00640-2","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:23:18Z","timestamp":1782944598000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Obesity-driven extracellular vesicle signaling in cancer: mechanistic insights and clinical implications"],"prefix":"10.1038","volume":"15","author":[{"given":"Lakshmi Narasimhan","family":"Chakrapani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Velasquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshika","family":"Suresh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subasri Durga","family":"Sridhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0373-0607","authenticated-orcid":false,"given":"Ramya","family":"Sankaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suriya Prakash","family":"Arivazhagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Shanmugam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana Deepa Priya","family":"Dorayappan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"O\u2019Malley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thangavel","family":"Muthusamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8016-9134","authenticated-orcid":false,"given":"Karuppaiyah","family":"Selvendiran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"640_CR1","doi-asserted-by":"crossref","unstructured":"Ingram Y, Olujide O, Sheikh N, Robinson A, Ho JH, Syed AA, et al. 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