{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T09:06:27Z","timestamp":1789635987057,"version":"4.0.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Type 2 diabetes mellitus and metabolic dysfunction associated steatotic liver disease contribute to the growing burden of hepatocellular carcinoma, yet their effects on hepatic antitumor immunity remain incompletely defined. Recent single-cell and spatial profiling studies indicate that hepatocellular carcinoma contains diverse CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell states, including cytotoxic, exhausted, tissue-resident, progenitor-like, and transitional phenotypes. This review synthesizes evidence linking hyperglycemia, insulin resistance, lipotoxic injury, chronic inflammation, fibrosis, altered antigen presentation, stromal remodeling, chemokine signaling, and nutrient availability to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell remodeling in HCC arising in the context of metabolic dysfunction. Particular attention is given to GZMK\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, which may reflect non-terminal differentiation, inflammatory adaptation, or transitional immune states rather than conventional cytotoxic effector function. Although GZMK-high CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell populations have been reported in hepatocellular carcinoma and therapy-associated immune contexts, direct evidence that type 2 diabetes induces these cells in the liver remains limited. This review specifically examines GZMK\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell states within the immunometabolic context of HCC, distinguishes direct hepatic and tumor evidence from extrapolated findings in metabolic liver disease and other inflammatory conditions, and proposes a testable framework for phenotypic, spatial, and functional validation. Integrated single-cell, spatial, protein level, T cell receptor clonality, functional, and clinical studies are needed to define their biological significance and translational value.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1963310","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:52:48Z","timestamp":1789635168000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review"],"prefix":"10.3389","volume":"17","author":[{"given":"Qianqian","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Pathology, Medical School of Nantong University","place":["Nantong, Jiangsu, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Sixth Affiliated Hospital of Nantong University","place":["Yanchen, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juling","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical School of Nantong University","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J 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