{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:03:09Z","timestamp":1790845389040,"version":"4.1.0"},"reference-count":192,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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>Interferon-\u03b3 (IFN-\u03b3) confronts the field with an apparent contradiction that is better understood as a causal consequence: the cytokine most central to antitumor immunity is also a principal driver of immune escape, and recombinant IFN-\u03b3 has both helped and harmed patients. We argue that this duality is not paradoxical but expected, escape is, in large part, the predictable evolutionary outcome of effective IFN-\u03b3\u2013mediated pressure. The prevailing \u201ctwo faces\u201d framing, which separates antitumor and protumor effects by dose and duration, names this discrepancy without explaining what couples its halves. Here, we reframe IFN-\u03b3 as a time-ordered IFN-\u03b3 Response Cycle: a recurring causal motif, productive execution, a self-limiting turn, and selectable resistance, running around one tunable IFNGR\u2013JAK\u2013STAT1\u2013IRF1 backbone. We use \u201ccycle\u201d deliberately and in a restricted sense: not to imply that an individual tumor clone oscillates between sensitive and resistant states, but that this execute\u2013feedback\u2013select motif recurs across a tumor\u2019s heterogeneous clonal population and across successive rounds of immune pressure and therapy. Its reversible arc, adaptive feedback and non-genetic gating, can be therapeutically reopened, whereas genetic loss of the pathway constitutes a one-way exit from the cycle rather than a return within it. Its behavior is set less by signal magnitude than by decoding, which cells read the cytokine, at what intensity, in what spatial arrangement, and over what kinetics. Synthesizing evidence across tumor killing, antigen presentation, the cellular decoding network, adaptive and chronic feedback, genetic escape and induced phenotypic adaptation, therapeutic re-engineering, and biomarkers, we argue that resistance is largely manufactured by the very signaling that mediates control: by eliminating sensitive clones, IFN-\u03b3 selects for resistant clones. This recasts IFN-\u03b3 as a self-defeating selective force and reframes the therapeutic goal as decoupling killing from selection, preserving execution while severing the feedback and selection arc. IFN-\u03b3 biomarkers currently report the presence and dominance of an inflammatory, IFN-\u03b3-driven state rather than a defined position within the cycle; longitudinal, spatial, and compartment-resolved measurements may eventually permit a finer classification.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1954319","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:53:45Z","timestamp":1790844825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The IFN-\u03b3 response cycle: decoupling tumor killing from evolutionary selection in cancer immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Baiyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Jilin Cancer Hospital","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Jilin Cancer Hospital","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehan","family":"Ma","sequence":"additional","affiliation":[{"name":"First Surgery Department of Colorectal, Gastric, and Abdominal Tumors, Jilin Cancer Hospital","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Sui","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Women\u2019s Hospital, School of Medicine, Zhejiang University, Jilin Hospital","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.17179\/excli2025-8617","article-title":"IFN-gamma in the tumor 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