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Tumor metabolic adaptation is emerging as a key factor limiting immunotherapy efficacy. We previously found that glycolysis-low tumor variants, compared to the parental glycolytic tumors, better respond to neoadjuvant CTLA-4 immune checkpoint blockade (ICB) therapy. Here, we investigated new rational modalities to restore immune sensitivity of glycolytic tumors by studying how lowering the tumor-cell glycolytic capacity reshapes the tumor microenvironment (TME) to favor long-lasting systemic anti-tumor responses upon immunotherapy.<\/jats:p>\n                <jats:p>\n                  We found that lowering glycolysis in cancer cells through LDHA-knock down (KD) results in TME displaying normalized vasculature, reduced angiogenic markers, increased high endothelial venules (HEVs), and enhanced recirculation of CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells both in and out of the tumor. By leveraging public transcriptomic data sets from human solid cancers, we confirmed that glycolysis positively correlates with neo-angiogenesis and inversely correlates with features of vascular normalization and immune cytolytic activity. Moreover, a tumor signature that incorporates glycolysis- and angiogenesis-related genes as positive features, and normal vasculature, HEV, and immune cytolytic activity genes as negative features predicted poor outcomes better than the individual features across most human solid tumor types in the TCGA. To determine the therapeutic implication of these interrelated processes, we asked if targeting the vasculature would restore immunotherapy responses in glycolytic tumors. We found that combining low-dose anti-VEGFR2 with CTLA-4 blockade induces tumor regressions and protection from metastases in glycolytic tumors. These therapeutic effects were associated with vasculature normalization and increased abundance of HEVs and concentrations of lymphangiogenic factors in the TME of glycolytic tumors. Moreover, anti-VEGFR2 with anti-CTLA-4 restored recirculation of anti-tumor CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in and out of the TME in glycolytic tumors, with specific increases in intratumoral recruitment and activation of cytolytic CD62L\u207aCD44\u207aCD8\u207a T cells expressing VEGFR2 and low levels of CTLA-4, suggesting potential novel direct synergistic effects of anti-VEGFR2 and anti-CTLA-4 on CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells. Conversely, this combination opposed the beneficial immune and vascular TME features of LDHA-KD tumors, indicating tumor-metabolic-dependent effects. Accordingly, we found that standard combined regimens of anti-VEGF and ICB therapy improve survival with respect to ICB alone in patients with glycolysis-high but not glycolysis-low tumors.\n                <\/jats:p>\n                <jats:p>Together, these findings indicate that tumor cell glycolysis \u201cprimes\u201d the TME for aberrant vascular architecture and T-cell exclusion, and that modulating the tumor vasculature can unravel these mechanisms restoring immune responsiveness. This suggests that tailoring anti-angiogenic and immunotherapy combinations to the tumor glycolytic state and associated vasculature profiles may restore immune surveillance and overcome therapy resistance.<\/jats:p>","DOI":"10.64898\/2026.02.23.707524","type":"posted-content","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T06:40:12Z","timestamp":1772001612000},"source":"Crossref","is-referenced-by-count":1,"title":["A tumor metabolism-angiogenesis-immune axis governs immunotherapy responses"],"prefix":"10.64898","author":[{"given":"Inna","family":"Serganova","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"},{"name":"Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8280-2589","authenticated-orcid":false,"given":"Giorgia","family":"Colombo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ballesio","sequence":"additional","affiliation":[{"name":"University of Tor Vergata, Rome, Italy"},{"name":"Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo (Norway)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee Hye","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"},{"name":"Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triantafyllia","family":"Karakousi","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tullio V. F.","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Ackerstaff","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065"},{"name":"MD Anderson Cancer Center, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Santella","sequence":"additional","affiliation":[{"name":"Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Blasberg","sequence":"additional","affiliation":[{"name":"Department of Neurology, Emeritus Professor, Memorial Sloan Kettering Cancer Center, New York, NY 10065"},{"name":"Molecular Pharmacology Program, Emeritus Professor, Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naga Vara Kishore","family":"Pillarsetty","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065"},{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Schreier","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"},{"name":"Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Andreopoulou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"},{"name":"Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Demaria","sequence":"additional","affiliation":[{"name":"Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021"},{"name":"Department of Pathology, Weill Cornell Medicine, New York, NY 10021"},{"name":"Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7389-9983","authenticated-orcid":false,"given":"Amanda W.","family":"Lund","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Federico","family":"Gherardini","sequence":"additional","affiliation":[{"name":"University of Tor Vergata, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Zappasodi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medical College, New York, NY 10021"},{"name":"Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021"},{"name":"Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10021"},{"name":"Parker Institute for Cancer Immunotherapy @Weill Cornell Medicine, Weill Cornell Medicine, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026022612051162000_2026.02.23.707524v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"2026022612051162000_2026.02.23.707524v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01141-1"},{"key":"2026022612051162000_2026.02.23.707524v1.3","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0041"},{"key":"2026022612051162000_2026.02.23.707524v1.4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3649"},{"key":"2026022612051162000_2026.02.23.707524v1.5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.66.7220"},{"key":"2026022612051162000_2026.02.23.707524v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.10.016"},{"key":"2026022612051162000_2026.02.23.707524v1.7","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0433"},{"key":"2026022612051162000_2026.02.23.707524v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1406498"},{"key":"2026022612051162000_2026.02.23.707524v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348"},{"key":"2026022612051162000_2026.02.23.707524v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature22079"},{"key":"2026022612051162000_2026.02.23.707524v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.10.007"},{"key":"2026022612051162000_2026.02.23.707524v1.12","unstructured":"Serganova, I. & Zappasodi, R. 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