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We developed a radio-immunotherapy regimen that can cure large immunologically hot and cold murine tumors. Here, we explored the divergent role of CD8 T cells during this radio-immunotherapy in contrasting hot colon carcinoma versus cold melanoma. We introduced an immunocompetent mouse model with mCherry-expressing CD8 T cells to provide cell tracking\n                  <jats:italic>in vivo<\/jats:italic>\n                  . We investigated single-cell function, metabolism, and gene expression temporal changes using flow cytometry,\n                  <jats:italic>in vivo<\/jats:italic>\n                  multiphoton imaging, single-cell RNA sequencing, and multiplexed immunofluorescence to determine the underlying mechanisms. We found that in contrast to the hot colon carcinoma model, CD8 T cells from the cold melanoma model do not drive tumor cures, despite getting activated, possibly due to a static oxidative metabolism and exhausted phenotype plus down regulation of tumor MHC-I expression. These findings have implications for improving immunotherapy response in immunologically cold cancers.\n                <\/jats:p>","DOI":"10.1101\/2025.10.24.684274","type":"posted-content","created":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T09:55:12Z","timestamp":1761472512000},"source":"Crossref","is-referenced-by-count":1,"title":["Divergent role of CD8 T cells with distinct metabolic phenotypes during curative radio-immunotherapy in hot versus cold tumors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4144-5535","authenticated-orcid":false,"given":"Alexa R.","family":"Heaton","sequence":"first","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI, USA"},{"name":"Department of Human Oncology, University of Wisconsin, Madison, WI, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin, Madison, WI, US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel 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