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Here we analyze the NSCLC tumor microenvironment (TME) using multiplexed immunofluorescence (mIF) of biopsies taken from patients prior to ICI treatment. We apply a deep-learning model to classify the cellular phenotypes and probe functional and metabolic states of both tumor and immune cells, aiming to reveal predictive features of response to ICI. Tissue neighborhoods are generated to allow geometric profiling of spatial densities and interactions at a range of scales. Multivariate modelling of ICI response yields a model that predicts progression-free survival (PFS) over 24 months (AUC\u2009=\u20090.8). The selected features in the model imply a role for cell-cell proximities within discrete metabolic contexts. These tissue insights may supplement our understanding of the current paradigms around classical immunology in the NSCLC TME and its influence on immunotherapy outcomes.<\/jats:p>","DOI":"10.1038\/s41467-026-68633-8","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T10:03:24Z","timestamp":1770113004000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic characterization of tumor-immune interactions by multiplexed immunofluorescence reveals spatial mechanisms of immunotherapy response in non-small cell lung carcinoma (NSCLC)"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-8402","authenticated-orcid":false,"given":"James","family":"Monkman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1450-0009","authenticated-orcid":false,"given":"Aaron","family":"Kilgallon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7208-9225","authenticated-orcid":false,"given":"Clara","family":"Lawler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Tubelleza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-0426","authenticated-orcid":false,"given":"Thazin Nwe","family":"Aung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1323-4602","authenticated-orcid":false,"given":"Jonathan H.","family":"Warrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-5986","authenticated-orcid":false,"given":"Ioannis","family":"Vathiotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis P.","family":"Trontzas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-6831","authenticated-orcid":false,"given":"Niki","family":"Gavrielatou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1633-6125","authenticated-orcid":false,"given":"Nay Nwe","family":"Nyein Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Czertok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5132-4024","authenticated-orcid":false,"given":"Shai","family":"Bookstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"O\u2019Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettai","family":"Markovits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-4397","authenticated-orcid":false,"given":"David L.","family":"Rimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7350","authenticated-orcid":false,"given":"Arutha","family":"Kulasinghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"68633_CR1","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1126\/science.aar4060","volume":"359","author":"A Ribas","year":"2018","unstructured":"Ribas, A. & Wolchok, J. 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Amgen, Cepheid, NavigateBP, NextCure, and Konica Minolta fund or have funded research in DLR\u2019s laboratory. R.C. was an employee of Nucleai at the time this work was conducted. S.B. and E.M. are current employees of Nucleai. A.K. is on the Scientific Advisory Board for Omapix Solutions, European Spatial Biology Centre, Predxbio, Molecular Instruments and Visiopharm. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"837"}}