{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:04:42Z","timestamp":1793253882321,"version":"4.5.0"},"reference-count":106,"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                    IL\u20132 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T\u2013cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL\u20132 has represented a landmark in cancer immunotherapy. However, high\u2013dose (HD) IL\u20132 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL\u20132\u2019s dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next\u2013generation IL\u20132 variants (IL\u20132v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD\u20131\n                    <jats:sup>+<\/jats:sup>\n                    TCF\u20131\n                    <jats:sup>+<\/jats:sup>\n                    stem\u2013like CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells have recently been identified as a key population sustaining long\u2013term antitumor immunity. TCF\u20131 is a transcription factor associated with a less differentiated, self\u2013renewing state and marks this progenitor\u2013exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor\u2013exhausted cells retain stem\u2013like properties, self\u2013renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL\u20132 and are central mediators of the synergy observed between IL\u20132 signaling and PD\u20131 blockade. Mechanistically, PD\u20131 inhibition releases inhibitory constraints, while IL\u20132 provides a potent STAT5\u2013driven proliferative and differentiation signal that expands the stem\u2013like CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2013cell pool and generates functional effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. This review summarizes IL\u20132 biology, the limitations of high\u2013dose IL\u20132 (HD IL\u20132) therapy, and emerging strategies, including CD25\u2013 or CD122\u2013biased IL\u20132 variants, tumor\u2013targeted IL\u20132 prodrugs, and IL\u20132\u2013based combination therapies designed to harness IL\u20132\u2019s antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem\u2013like CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells as key mediators of therapeutic efficacy.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1756987","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:52:38Z","timestamp":1789635158000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Advances in IL\u20132\u2013based cancer immunotherapy and the synergistic role of stem\u2013like CD8+ T cells in IL\u20132 and PD\u20131 combination therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Huiquan","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Radiotherapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University","place":["Yantai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Affiliated Weihai Second Municipal Hospital of Qingdao University","place":["Weihai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiru","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Affiliated Weihai Second Municipal Hospital of Qingdao University","place":["Weihai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxiu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The Affiliated Weihai Second Municipal Hospital of Qingdao University","place":["Weihai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg","place":["Freiburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.181845","article-title":"Selective in vitro growth of T lymphocytes from normal human bone marrows","volume":"193","author":"Morgan","year":"1976","journal-title":"Sci (New York NY)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1716612","article-title":"Immunocytokines in cancer immunotherapy: opportunities and challenges","volume":"15","author":"Wang","year":"2026","journal-title":"Front 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