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Here, we investigated the effects of tumor-derived VEGF-C on the therapeutic efficacy of oncolytic virotherapy with avian paramyxoviruses APMV-1 (NDV) and AMPV-4. Treatment of B16F10 tumors not expressing VEGF-C with either virus led to tumor growth delay, and complete responses were rare. In contrast, when tumors expressed VEGF-C, viral therapy led to complete remission and long-term immunological memory in most mice. Upon re-challenge, most mice remained tumor- and metastasis-free for over 18 months, indicating durable immunity. VEGF-C induced tumor lymphangiogenesis, which correlated with high CD8\n                  <jats:sup>+<\/jats:sup>\n                  and CD4\n                  <jats:sup>+<\/jats:sup>\n                  T-cell densities in proximity of lymphatic vessels. Spectral flow cytometry revealed distinct changes in the composition and activation of CD8\n                  <jats:sup>+<\/jats:sup>\n                  , CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells and NK cells associated with complete remission. In responders, tumors were highly enriched in CD8\n                  <jats:sup>+<\/jats:sup>\n                  CD25\n                  <jats:sup>+<\/jats:sup>\n                  PD-1\n                  <jats:sup>+<\/jats:sup>\n                  effector T cells. Composition of T cells was altered in sentinel and in contralateral lymph nodes, indicating a systemic immune response. Taken together, these data demonstrate VEGF-C-induced changes in tumor immune landscape which are critical for achieving complete response and support combining VEGF-C with APMV virotherapy as a novel highly effective strategy for cancer treatment.\n                <\/jats:p>","DOI":"10.1101\/2025.08.27.672466","type":"posted-content","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T15:50:15Z","timestamp":1756741815000},"source":"Crossref","is-referenced-by-count":1,"title":["Lymphangiogenesis driven by VEGF-C reshapes tumor immune landscape and enables tumor eradication by viral immunotherapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9127-1735","authenticated-orcid":false,"given":"Ruben","family":"Fernandez-Rodriguez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9400-746X","authenticated-orcid":false,"given":"Sara","family":"Cuadrado-Castano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-5159","authenticated-orcid":false,"given":"Anita","family":"Rogic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0834-0953","authenticated-orcid":false,"given":"Yonina","family":"Bykov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-7086","authenticated-orcid":false,"given":"Ignacio","family":"Mena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9633-1749","authenticated-orcid":false,"given":"Noelia","family":"Dasilva-Freire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9230-9501","authenticated-orcid":false,"given":"Alice O","family":"Kamphorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Karlic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Horowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6551-1827","authenticated-orcid":false,"given":"Adolfo","family":"Garc\u00eda-Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1583-6487","authenticated-orcid":false,"given":"Mihaela","family":"Skobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025090514101429000_2025.08.27.672466v2.1","unstructured":"Y. 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