{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T02:14:31Z","timestamp":1770516871738,"version":"3.49.0"},"reference-count":111,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002583","name":"Gyeongsang National University","doi-asserted-by":"crossref","award":["GNU-NFRSG-0041"],"award-info":[{"award-number":["GNU-NFRSG-0041"]}],"id":[{"id":"10.13039\/501100002583","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002583","name":"Gyeongsang National University Hospital","doi-asserted-by":"crossref","award":["GNUHBRIF-2025-0001"],"award-info":[{"award-number":["GNUHBRIF-2025-0001"]}],"id":[{"id":"10.13039\/501100002583","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Colorectal cancer (CRC) cachexia is a multifactorial, treatment-limiting syndrome characterized by progressive loss of skeletal muscle with or without loss of fat mass, accompanied by systemic inflammation, anorexia, metabolic dysregulation, and impaired treatment tolerance. Despite decades of work, cachexia remains clinically underdiagnosed and therapeutically underserved, in part because canonical models treat tumor-derived factors and host inflammatory mediators as a largely \u2018host-only\u2019 network. In parallel, CRC is strongly linked to intestinal dysbiosis, barrier disruption, and microbial translocation. Extracellular vesicles (EVs)\u2014host small EVs, tumor-derived EVs, and bacterial extracellular vesicles (including outer membrane vesicles)\u2014may provide a mechanistically plausible, information-dense route by which these domains could be coupled. Here, we synthesize emerging evidence suggesting that cross-kingdom EV signaling may operate as a vesicular ecosystem spanning gut lumen, mucosa, circulation, and peripheral organs. We propose the \u201cvesicular intersection layer\u201d as a unifying framework for how heterogeneous EV cargos converge on shared host decoding hubs (e.g., pattern-recognition receptors and stress-response pathways) to potentially contribute to muscle catabolism. We critically evaluate what is known\u2014and what remains unproven\u2014about EV biogenesis, trafficking, and causal mechanisms in CRC cachexia, highlight methodological constraints in microbial EV isolation and attribution, and outline minimum evidentiary standards for cross-kingdom claims. Finally, we translate the framework into actionable hypotheses for EV-informed endotyping, biomarker development (including stool EV assays), and therapeutic strategies targeting shared signaling nodes (e.g., TLR4\u2013p38) and endocrine mediators that are predominantly soluble but may be fractionally vesicle-associated (e.g., GDF15). By reframing CRC cachexia as an emergent property of tumor\u2013host\u2013microbiota vesicular communication, this review provides a roadmap for mechanistic studies and clinically tractable interventions.<\/jats:p>","DOI":"10.3390\/cancers18030522","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T15:24:19Z","timestamp":1770305059000},"page":"522","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Vesicular Intersection Layer: A Framework for Cross-Kingdom Extracellular Vesicle Signaling That May Connect Gut Dysbiosis to Skeletal Muscle Wasting in Colorectal Cancer Cachexia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-2722","authenticated-orcid":false,"given":"Young-Sool","family":"Hah","sequence":"first","affiliation":[{"name":"Department of Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, Jinju 52725, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeongyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, Jinju 52725, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-9158","authenticated-orcid":false,"given":"Seung-Jin","family":"Kwag","sequence":"additional","affiliation":[{"name":"Department of Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.12998\/wjcc.v8.i7.1188","article-title":"Sarcopenia in patients with colorectal cancer: A comprehensive review","volume":"8","year":"2020","journal-title":"World J. 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