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This review systematically examines, for the first time, the meningeal lymphatic vessel\u2013peripheral immune axis as an integrated framework linking central proteinopathy, neuroinflammation, and systemic immune responses in neurodegenerative diseases. We highlight recent therapeutic advances, including lymphatic regeneration via the VEGF-C pathway, peripheral immune modulation, and combinatorial approaches. We also discuss current challenges and future translational directions, emphasizing the need for integrating lymphatic imaging with immune phenotyping to enable personalized interventions. While the majority of evidence discussed derives from preclinical models, we critically evaluate its translational relevance and highlight unresolved controversies. Based on the evidence, we propose that targeting this axis offers a dual opportunity to enhance CNS waste clearance and restore immune tolerance, providing a promising framework for clinical management.<\/jats:p>","DOI":"10.1186\/s12974-026-03849-5","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:26:21Z","timestamp":1777861581000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The meningeal lymphatic vessel\u2013peripheral immune axis: a novel therapeutic target in neurodegenerative diseases"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9994-8720","authenticated-orcid":false,"given":"Zhidong","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2454-5553","authenticated-orcid":false,"given":"Jing","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"3849_CR1","doi-asserted-by":"publisher","first-page":"1664269","DOI":"10.3389\/fnagi.2025.1664269","volume":"17","author":"VFB Macedo","year":"2025","unstructured":"Macedo VFB, Macedo VKB, de Miranda Coelho JAP, de Melo Barboza AM. 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