{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:02:58Z","timestamp":1789390978254,"version":"build-2803163510"},"reference-count":174,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"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                    Recent studies have identified antigen-experienced TCF1\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    lineage-negative (lin\n                    <jats:sup>-<\/jats:sup>\n                    ) CD4 T cells in several tumor types. Strictly, stemness requires durable self-renewal and multipotent output demonstrated at the single-cell level; these criteria have not yet been established for an individual tumor-associated CD4 T cell. Operationally, this review uses \u201cstem-like CD4 T cells\u201d for TCF1\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    lin\n                    <jats:sup>-<\/jats:sup>\n                    populations that lack canonical terminal TH1, TH2, TH17, and Treg commitment programs and show population-level persistence and multilineage output. Pending single-cell lineage tracing, these populations are best regarded as candidate progenitor-like states. Within the tumor microenvironment, their differentiation trajectory may influence antitumor immunity. Treg-mediated suppression, TGF-\u03b2 signaling, metabolic stress, and limited IL-12 can restrain effector differentiation, whereas release of these constraints can permit TH1 output, CD8-supporting activity in tumor-draining lymph nodes, and direct MHC class II\u2013restricted antitumor effects in selected models. Direct tumor evidence remains concentrated in a limited set of studies, while infection, autoimmunity, transplantation, and CD8 research provide contextual or cross-lineage support. This review therefore presents stem-like CD4 biology as an emerging framework and distinguishes established observations from working models.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1853163","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:43:10Z","timestamp":1787830990000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiaxiang","family":"Xu","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunchao","family":"Yang","sequence":"additional","affiliation":[{"name":"Shandong College of Traditional Chinese Medicine","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-030409-101212","article-title":"Differentiation of effector CD4 T cell populations (*)","volume":"28","author":"Zhu","year":"2010","journal-title":"Annu Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0044-0","article-title":"CD4(+) T cell help in cancer immunology and 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