{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T04:27:09Z","timestamp":1792902429058,"version":"4.5.0"},"reference-count":124,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"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                    Interleukin-15 (IL-15) has emerged as a central cytokine for next-generation cancer immunotherapy because of its unique ability to sustain the survival, proliferation, and cytotoxic function of memory CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and natural killer (NK) cells without promoting the expansion of regulatory T cells (Treg). These properties make IL-15 particularly attractive for achieving durable antitumor immunity, especially in solid tumors where immune persistence remains a major limitation. Although IL-15 shares the same signal-transducing receptor subunits (IL-2R\n                    <jats:italic>\u03b2<\/jats:italic>\n                    and the common\n                    <jats:italic>\u03b3<\/jats:italic>\n                    chain) with interleukin-2 (IL-2), the two cytokines drive fundamentally different CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell fates, a distinction that underlies their markedly divergent therapeutic profiles in cancer immunotherapy. In recent years, multiple IL-15-based therapeutic strategies including recombinant IL-15, and IL-15 immunocytokines have entered clinical evaluation, demonstrating potent immune activation with manageable toxicity profiles. Recent clinical progress includes the FDA approval of Nogapendekin alfa inbakicept (N-803), the first IL-15-based immunotherapy approved for cancer treatment, alongside the advancement of other IL-15 superagonists into Phase II trials and growing evidence that IL-15 can enhance the efficacy of immune checkpoint blockade and engineered adoptive cell therapies such as CAR-T cells, CAR-NK cells,\n                    <jats:italic>\u03b3\u03b4<\/jats:italic>\n                    T cells, and invariant NKT cells. Despite these advances, important challenges remain, including cytokine-associated toxicities, optimal delivery strategies, and the immunosuppressive tumor microenvironment. This review summarizes recent progress in IL-15-based cancer immunotherapy, integrates emerging insights into IL-2R\n                    <jats:italic>\u03b2\u03b3<\/jats:italic>\n                    -driven CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell fate decisions, and discusses key opportunities and challenges for translating IL-15-mediated immune enhancement into durable clinical benefit.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1791059","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:02:44Z","timestamp":1775800964000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Advances in IL\u201315\u2013Based Cancer Immunotherapy and Divergent Immunological Effects of IL\u20132 and IL\u201315 Signaling via the Shared IL\u20132R\u03b2\u03b3 Receptor"],"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":"Tao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The 970th Hospital of the People\u2019s Liberation Army","place":["Weihai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The 970th Hospital of the People\u2019s Liberation Army","place":["Weihai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanfang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The 970th Hospital of the People\u2019s Liberation Army","place":["Weihai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Weihai Municipal Hospital","place":["Weihai, Shandong, 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, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The 970th Hospital of the People\u2019s Liberation Army","place":["Weihai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The 970th Hospital of the People\u2019s Liberation Army","place":["Weihai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wu","sequence":"additional","affiliation":[{"name":"Bioinformatics and Molecular Genetics, Faculty of Biology, University of Freiburg","place":["Freiburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University","place":["Shanghai, 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, 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