{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:17:56Z","timestamp":1788455876901,"version":"build-2803163510"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The clinical heterogeneity of colon adenocarcinoma (COAD) complicates patient prognosis and treatment. While metabolic reprogramming is a key driver of tumor progression, the role of histidine metabolism in the COAD immune microenvironment remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Through an integrated analysis of public single-cell and bulk transcriptomic data, we mapped the COAD cellular atlas and assessed histidine metabolism activity. A prognostic Histidine Metabolism-related Model (HRM) was constructed using an ensemble of 101 machine learning algorithms, and its biological underpinnings were explored. The function of the key gene, TRIP6, was validated via\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell analysis identified epithelial cells as the hub of histidine metabolism, which remodels TME intercellular communication. The machine learning-derived HRM robustly stratified patient prognosis across a primary and two validation cohorts. High HRM scores correlated with an \u201cinfiltrated-exhausted\u201d immune phenotype, characterized by high immune infiltration alongside elevated checkpoint expression. The key signature gene TRIP6 was identified as a driver of poor prognosis and an immunosuppressive state, and its silencing suppressed malignant phenotypes\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Histidine metabolism is a critical regulator of the COAD immune microenvironment. Our prognostic model, the HRM, provides a clinically relevant tool for risk stratification, while its key mediator, TRIP6, represents a novel therapeutic target linking tumor metabolism to immune evasion.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1719555","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T06:29:51Z","timestamp":1765175391000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A multi-omic machine learning approach deconstructs the role of amino acid metabolism in the immune microenvironment and prognosis of colon 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