{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T15:11:33Z","timestamp":1779289893001,"version":"3.51.4"},"reference-count":10,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"unspecified","delay-in-days":19,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,5,7]]},"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>Maintenance of anticancer immunity without compromising immune tolerance remains a challenge. Immunosuppressive regulatory T cells (Tregs) are the guardians of immune tolerance that underpin prevention of autoimmune responses. Tregs express checkpoint molecules that suppress autoreactive immune cells from being activated by endogenous (self) proteins. However, expression of these checkpoints on immune cells contributes to cancer cell evasion from the immune system while inhibition of checkpoint signaling in cancer immunotherapy induces autoimmune-related adverse events. Two instructive cytokines that regulate the opposing functions of immunosuppressive Tregs and anticancer responses mediated by cytotoxic natural killer cells include the interleukins, IL-2 and IL-12. An overview based on published data is described herein to highlight how manipulation of these cytokines may have dual action in oncologic and autoimmune models. This raises the possibility of exploiting mechanisms in cancer immunotherapy that could promote anticancer immunity while still maintaining immune tolerance. Given the role of peptides in protein-related interactions, it remains important in rational drug design to remain vigilant for potentially beneficial effects that could benefit both cancer surveillance and immune tolerance.<\/jats:p>","DOI":"10.1136\/jitc-2025-014602","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:15:19Z","timestamp":1779286519000},"page":"e014602","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Immune tolerance versus cancer surveillance: an ongoing challenge"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7650-6950","authenticated-orcid":false,"given":"Michael","family":"Agrez","sequence":"first","affiliation":[{"name":"InterK Peptide Therapeutics Limited, North Ryde, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"2026052007151307000_14.5.e014602.1","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2022-006500","article-title":"Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review","volume":"11","author":"Barron","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026052007151307000_14.5.e014602.2","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-15455-5","article-title":"A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses","volume":"12","author":"Agrez","year":"2022","journal-title":"Sci Rep"},{"key":"2026052007151307000_14.5.e014602.3","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines13081908","article-title":"An Immunomodulating Peptide with Potential to Promote Anticancer Immunity Without Compromising Immune Tolerance","volume":"13","author":"Agrez","year":"2025","journal-title":"Biomedicines"},{"key":"2026052007151307000_14.5.e014602.4","doi-asserted-by":"crossref","first-page":"1589042","DOI":"10.3389\/fimmu.2025.1589042","article-title":"First-in-human evaluation of a no-alpha interleukin\u20132 mutein: safety and preliminary pharmacodynamic and clinical effect","volume":"16","author":"Caballero Aguirrechu","year":"2025","journal-title":"Front Immunol"},{"key":"2026052007151307000_14.5.e014602.5","doi-asserted-by":"crossref","unstructured":"Calvo E , Boni V , Dumas O , et al . 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