{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:43:54Z","timestamp":1788389034658,"version":"build-2803163510"},"reference-count":10,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"unspecified","delay-in-days":23,"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":[[2025,12,4]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:p>Casitas B lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that serves as a critical brake on immune cell activations. It negatively fine-tunes immune responses through ubiquitination of signaling proteins. Cbl-b deficiency in mice leads to spontaneous tumor rejection and induces only mild, non-lethal autoimmunity, highlighting its potential as a promising immunotherapy target. NX-1607 is the first oral small molecule inhibitor of Cbl-b and it is currently in phase I clinical trial. A recent publication employed high-throughput drug combination screening to systematically elucidate the molecular pathways by which NX-1607 enhances T cell activation. The authors administered 81 well-characterized inhibitors to Jurkat T cells under CD3-stimulated and unstimulated conditions in the presence of NX-1607. Inhibitors of the MAPK\/ERK pathway significantly attenuated NX-1607-enhanced T cell activation as indicated by CD69 markers. Proto-oncogene tyrosine-protein kinase Src (SRC) family kinase inhibitors also reduced both CD69 activation markers and the phosphorylation of PLC\u03b31 and HCLS1 which are upstream of MAPK\/ERK pathways. These findings were validated in an immunocompetent B-cell lymphoma mouse model, where NX-1607 consistently upregulated PLC\u03b31 and ERK phosphorylation. Together, this work delineates a PLC\u03b31-MAPK\/ERK axis through which Cbl-b inhibition unleashes T cell activation, providing critical insight for the development of NX-1607 based immunotherapy.<\/jats:p>","DOI":"10.1136\/jitc-2025-012979","type":"journal-article","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T10:00:23Z","timestamp":1766656823000},"page":"e012979","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["NX-1607: lifting the Cbl-b brake to promote T cell activation through MAPK\/ERK pathways"],"prefix":"10.1136","volume":"13","author":[{"given":"Alex","family":"To","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5701-3628","authenticated-orcid":false,"given":"Ryohichi","family":"Sugimura","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, University of Hong Kong, Hong Kong, Hong Kong"},{"name":"Centre for Translational Stem Cell Biology, University of Hong Kong, Hong Kong, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"2025122502001772000_13.12.e012979.1","doi-asserted-by":"crossref","DOI":"10.1038\/s42003-023-05655-8","article-title":"The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition","volume":"6","author":"Kimani","year":"2023","journal-title":"Commun Biol"},{"key":"2025122502001772000_13.12.e012979.2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/35003235","article-title":"Cbl-b regulates the CD28 dependence of T-cell activation","volume":"403","author":"Chiang","year":"2000","journal-title":"Nature New Biol"},{"key":"2025122502001772000_13.12.e012979.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature12998"},{"key":"2025122502001772000_13.12.e012979.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.03.015"},{"key":"2025122502001772000_13.12.e012979.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2109970"},{"key":"2025122502001772000_13.12.e012979.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.008"},{"key":"2025122502001772000_13.12.e012979.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.05.002"},{"key":"2025122502001772000_13.12.e012979.8","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.semcancer.2020.03.003","article-title":"ITCH as a potential therapeutic target in human cancers","volume":"67","author":"Yin","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"2025122502001772000_13.12.e012979.9","doi-asserted-by":"crossref","unstructured":"Gallotta M , Gosling J , Tenn-McClellan A , et al . 824\u2005NX-1607, a small molecule inhibitor of the cbl-b e3 ubiquitin ligase, promotes t and nk cell activation and enhances nk-mediated adcc in a mouse lymphoma tumor model. SITC 37th Annual Meeting (SITC 2022) Abstracts; November 2022 doi:10.1136\/jitc-2022-SITC2022.0824","DOI":"10.1136\/jitc-2022-SITC2022.0824"},{"key":"2025122502001772000_13.12.e012979.10","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-011180","article-title":"Cbl-b inhibitor NX-1607 activates MAPK\/ERK signaling pathway and enhances T-cell activation","volume":"13","author":"Zhu","year":"2025","journal-title":"J Immunother Cancer"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-012979","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T10:00:24Z","timestamp":1766656824000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-012979"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":10,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,25]]},"published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1136\/jitc-2025-012979"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-012979","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]}}}