{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:53:50Z","timestamp":1782924830671,"version":"3.54.5"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":34,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2025JJ70052"],"award-info":[{"award-number":["2025JJ70052"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"crossref","award":["2025JJ50493"],"award-info":[{"award-number":["2025JJ50493"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Major Scientific Research Project for High-level Talents in Health Care of Hunan Province","award":["R2023173"],"award-info":[{"award-number":["R2023173"]}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82303246"],"award-info":[{"award-number":["82303246"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Health Research Project of Hunan Provincial Health Commission","award":["W20243173"],"award-info":[{"award-number":["W20243173"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Digit. Med."],"DOI":"10.1038\/s41746-025-02286-7","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T04:44:10Z","timestamp":1767069850000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Machine learning-enabled spatial multi-omics uncovers lactate-driven targets and tumor microenvironmental reprogramming in cancer"],"prefix":"10.1038","volume":"9","author":[{"given":"Yingzheng","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenliang","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhu","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuanghua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangjing","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingli","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyuan","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueming","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyuan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anbo","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"2286_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41571-023-00733-6","volume":"20","author":"G Harada","year":"2023","unstructured":"Harada, G., Yang, S. R., Cocco, E. & Drilon, A. Rare molecular subtypes of lung cancer. Nat Rev Clin Oncol 20, 229\u2013249 (2023).","journal-title":"Nat Rev Clin Oncol"},{"key":"2286_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01740-y","volume":"22","author":"A Lahiri","year":"2023","unstructured":"Lahiri, A. et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer 22, 40 (2023).","journal-title":"Mol Cancer"},{"key":"2286_CR3","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s10555-024-10172-z","volume":"43","author":"GR Bhat","year":"2024","unstructured":"Bhat, G. R. et al. Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev 43, 197\u2013228 (2024).","journal-title":"Cancer Metastasis Rev"},{"key":"2286_CR4","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/s41591-021-01233-9","volume":"27","author":"I Vitale","year":"2021","unstructured":"Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med 27, 212\u2013224 (2021).","journal-title":"Nat Med"},{"key":"2286_CR5","doi-asserted-by":"publisher","first-page":"103579","DOI":"10.1016\/j.autrev.2024.103579","volume":"23","author":"C Chen","year":"2024","unstructured":"Chen, C., Han, P. & Qing, Y. Metabolic heterogeneity in tumor microenvironment - A novel landmark for immunotherapy. Autoimmun Rev 23, 103579 (2024).","journal-title":"Autoimmun Rev"},{"key":"2286_CR6","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/s42255-023-00963-z","volume":"6","author":"M Demicco","year":"2024","unstructured":"Demicco, M., Liu, X.-Z., Leithner, K. & Fendt, S.-M. Metabolic heterogeneity in cancer. Nat Metab 6, 18\u201338 (2024).","journal-title":"Nat Metab"},{"key":"2286_CR7","doi-asserted-by":"publisher","first-page":"808859","DOI":"10.3389\/fcell.2022.808859","volume":"10","author":"M Jin","year":"2022","unstructured":"Jin, M., Cao, W., Chen, B., Xiong, M. & Cao, G. Tumor-derived lactate creates a favorable niche for tumor via supplying energy source for tumor and modulating the tumor microenvironment. Front cell developmental Biol 10, 808859 (2022).","journal-title":"Front cell developmental Biol"},{"key":"2286_CR8","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/s41392-022-01151-3","volume":"7","author":"X Li","year":"2022","unstructured":"Li, X. et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther 7, 305 (2022).","journal-title":"Signal Transduct Target Ther"},{"key":"2286_CR9","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.immuni.2025.02.008","volume":"58","author":"A Llibre","year":"2025","unstructured":"Llibre, A., Kucuk, S., Gope, A., Certo, M. & Mauro, C. Lactate: A key regulator of the immune response. Immunity 58, 535\u2013554 (2025).","journal-title":"Immunity"},{"key":"2286_CR10","doi-asserted-by":"publisher","first-page":"3119375","DOI":"10.1155\/2022\/3119375","volume":"2022","author":"Y Gao","year":"2022","unstructured":"Gao, Y. et al. Tumor microenvironment: Lactic acid promotes tumor development. J Immunol Res 2022, 3119375 (2022).","journal-title":"J Immunol Res"},{"key":"2286_CR11","doi-asserted-by":"publisher","unstructured":"Barba, I., Carrillo-Bosch, L. & Seoane, J. Targeting the Warburg effect in cancer: Where do we stand? Int. J. Mol. Sci. 25, https:\/\/doi.org\/10.3390\/ijms25063142 (2024).","DOI":"10.3390\/ijms25063142"},{"key":"2286_CR12","doi-asserted-by":"publisher","unstructured":"Lv, X., Mao, Z., Sun, X. & Liu, B. Intratumoral heterogeneity in lung cancer. Cancers (Basel) 15, https:\/\/doi.org\/10.3390\/cancers15102709 (2023).","DOI":"10.3390\/cancers15102709"},{"key":"2286_CR13","doi-asserted-by":"publisher","first-page":"1564226","DOI":"10.3389\/fonc.2025.1564226","volume":"15","author":"H Cai","year":"2025","unstructured":"Cai, H., Zhang, F., Xu, F. & Yang, C. Metabolic reprogramming and therapeutic targeting in non-small cell lung cancer: Emerging insights beyond the Warburg effect. Front Oncol 15, 1564226 (2025).","journal-title":"Front Oncol"},{"key":"2286_CR14","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1007\/s00432-024-05777-4","volume":"150","author":"R Huang","year":"2024","unstructured":"Huang, R., Kang, T. & Chen, S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 150, 238 (2024).","journal-title":"J Cancer Res Clin Oncol"},{"key":"2286_CR15","doi-asserted-by":"publisher","first-page":"1366096","DOI":"10.3389\/fimmu.2024.1366096","volume":"15","author":"H Zhang","year":"2024","unstructured":"Zhang, H. et al. Integrative single-cell analysis of LUAD: elucidating immune cell dynamics and prognostic modeling based on exhausted CD8+ T cells. Front Immunol 15, 1366096 (2024).","journal-title":"Front Immunol"},{"key":"2286_CR16","doi-asserted-by":"publisher","unstructured":"Grant, G. & Ferrer, C. M. The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth. Trends Cell Biology, https:\/\/doi.org\/10.1016\/j.tcb.2025.05.006 (2025).","DOI":"10.1016\/j.tcb.2025.05.006"},{"key":"2286_CR17","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/nature13490","volume":"513","author":"OR Colegio","year":"2014","unstructured":"Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559\u2013563 (2014).","journal-title":"Nature"},{"key":"2286_CR18","doi-asserted-by":"publisher","first-page":"1208870","DOI":"10.3389\/fimmu.2023.1208870","volume":"14","author":"H Tao","year":"2023","unstructured":"Tao, H., Zhong, X., Zeng, A. & Song, L. Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy. Front Immunol 14, 1208870 (2023).","journal-title":"Front Immunol"},{"key":"2286_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02138-7","volume":"23","author":"L Zheng","year":"2025","unstructured":"Zheng, L. et al. Cancer\u2011associated fibroblasts: a pivotal regulator of tumor microenvironment in the context of radiotherapy. Cell Commun Signal 23, 147 (2025).","journal-title":"Cell Commun Signal"},{"key":"2286_CR20","doi-asserted-by":"publisher","unstructured":"Wright, K., Ly, T., Kriet, M., Czirok, A. & Thomas, S. M. Cancer-associated fibroblasts: Master tumor microenvironment modifiers. Cancers (Basel) 15, https:\/\/doi.org\/10.3390\/cancers15061899 (2023).","DOI":"10.3390\/cancers15061899"},{"key":"2286_CR21","doi-asserted-by":"publisher","first-page":"103209","DOI":"10.1016\/j.redox.2024.103209","volume":"74","author":"X Gu","year":"2024","unstructured":"Gu, X. et al. Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression. Redox Biol 74, 103209 (2024).","journal-title":"Redox Biol"},{"key":"2286_CR22","doi-asserted-by":"publisher","first-page":"e3573","DOI":"10.1002\/jgm.3573","volume":"26","author":"M Zhang","year":"2024","unstructured":"Zhang, M., Liang, Y. & Song, P. COL3A1-positive endothelial cells influence LUAD prognosis and regulate LUAD carcinogenesis by NCL-PI3K-AKT axis. J Gene Med. 26, e3573 (2024).","journal-title":"J Gene Med."},{"key":"2286_CR23","doi-asserted-by":"publisher","first-page":"e109890","DOI":"10.15252\/embj.2021109890","volume":"41","author":"HW Lee","year":"2022","unstructured":"Lee, H. W. et al. Endothelium-derived lactate is required for pericyte function and blood\u2013brain barrier maintenance. EMBO J 41, e109890 (2022).","journal-title":"EMBO J"},{"key":"2286_CR24","doi-asserted-by":"publisher","first-page":"eadc9465","DOI":"10.1126\/sciadv.adc9465","volume":"9","author":"M Fan","year":"2023","unstructured":"Fan, M. et al. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction. Sci Adv 9, eadc9465 (2023).","journal-title":"Sci Adv"},{"key":"2286_CR25","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/s41392-024-02082-x","volume":"10","author":"J Chen","year":"2025","unstructured":"Chen, J. et al. Lactate and lactylation in cancer. Signal Transduct Target Ther 10, 38 (2025).","journal-title":"Signal Transduct Target Ther"},{"key":"2286_CR26","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1007\/s43440-023-00504-1","volume":"75","author":"M Jaworska","year":"2023","unstructured":"Jaworska, M. et al. The Warburg effect: A score for many instruments in the concert of cancer and cancer niche cells. Pharmacol Rep 75, 876\u2013890 (2023).","journal-title":"Pharmacol Rep"},{"key":"2286_CR27","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nri.2017.145","volume":"18","author":"Y Huang","year":"2018","unstructured":"Huang, Y. et al. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 18, 195\u2013203 (2018).","journal-title":"Nat Rev Immunol"},{"key":"2286_CR28","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41388-024-03228-5","volume":"44","author":"K Kane","year":"2025","unstructured":"Kane, K., Edwards, D. & Chen, J. The influence of endothelial metabolic reprogramming on the tumor microenvironment. Oncogene 44, 51\u201363 (2025).","journal-title":"Oncogene"},{"key":"2286_CR29","doi-asserted-by":"publisher","first-page":"1367875","DOI":"10.3389\/fimmu.2024.1367875","volume":"15","author":"P Leone","year":"2024","unstructured":"Leone, P. et al. Endothelial cells in tumor microenvironment: Insights and perspectives. Front Immunol 15, 1367875 (2024).","journal-title":"Front Immunol"}],"container-title":["npj Digital Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41746-025-02286-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41746-025-02286-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41746-025-02286-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T14:44:30Z","timestamp":1770043470000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41746-025-02286-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2286"],"URL":"https:\/\/doi.org\/10.1038\/s41746-025-02286-7","relation":{},"ISSN":["2398-6352"],"issn-type":[{"value":"2398-6352","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]},"assertion":[{"value":"9 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"109"}}