{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:18:08Z","timestamp":1783577888668,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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>Hepatocellular carcinoma (HCC) is associated with poor prognosis and limited responses to immunotherapy, partly due to the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages, especially M2-like macrophages, play important roles in HCC progression. Interleukin-4-induced gene 1 (IL4I1), a tryptophan-metabolizing enzyme, has been implicated in tumor immune regulation. However, the role and prognostic significance of IL4I1-expressing M2-like macrophages in HCC remain unclear. This study investigated the expression pattern, spatial distribution, functional association, and prognostic relevance of IL4I1-expressing M2-like macrophages in HCC and their association with patient outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed public databases (TIMER, UALCAN, TISCH2) for gene expression and prognostic significance. An\n                      <jats:italic>in vitro<\/jats:italic>\n                      co-culture system was established using a Huh7 HCC cell line and THP-1-derived M2-like macrophages with and without IL4I1 knockout via CRISPR\/Cas9. We assessed cell proliferation, migration, apoptosis, and cytokine profiles. Multiplex immunofluorescence (mIF) was performed on tissue microarrays from 92 HCC patients to analyze the spatial distribution of IL4I1+ M2-like macrophages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      IL4I1 was highly expressed in HCC, predominantly within macrophages, and correlated with poor prognosis. In a THP-1-derived macrophage\/Huh7 co-culture model, IL4I1 expression in M2-like macrophages was associated with increased Huh7 cell proliferation and migration and reduced apoptosis. This was associated with increased secretion of pro-inflammatory cytokines (e.g., CCL15, TNF-\u03b1) and decreased levels of IL-10 and TGF-\u03b21. mIF analysis further showed that a high density of IL4I1+ M2-like macrophages in the epithelial\/parenchymal tumor region was significantly associated with poorer overall survival (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.033).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IL4I1+ M2-like macrophages are associated with a pro-tumorigenic microenvironment and adverse patient outcomes in HCC. Our findings support IL4I1+ M2-like macrophages as a prognostically relevant macrophage subset, while further mechanistic validation, particularly of IL4I1-derived metabolites and AHR pathway activation, is required before IL4I1 can be considered a validated therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1872272","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:36:14Z","timestamp":1783575374000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of IL4I1+ M2-like macrophages in tumor microenvironment with poor prognosis in hepatocellular carcinoma: insights from bioinformatics and experimental validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Tao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical 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