{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:08:15Z","timestamp":1792789695387,"version":"4.5.0"},"reference-count":15,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T00:00:00Z","timestamp":1756252800000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/National Cancer Institute","award":["CA294168"],"award-info":[{"award-number":["CA294168"]}]},{"name":"Normunity Inc.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100002519","name":"United Technologies Corporation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100002519","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,8,1]]},"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Cancer immunotherapy targeting the PD-1\/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other \u2018checkpoint inhibitors\u2019 targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance\u2014but not redundancy\u2014of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.<\/jats:p>","DOI":"10.1136\/jitc-2025-012457","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:20:35Z","timestamp":1756315235000},"page":"e012457","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Why has immune \u201ccheckpoint\u201d therapy failed in most clinical trials?"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-7705","authenticated-orcid":false,"given":"Xuan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, Connecticut, USA"},{"name":"Yale University Yale Cancer Center, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"2025110500400948000_13.8.e012457.1","doi-asserted-by":"publisher","DOI":"10.1038\/nm730"},{"key":"2025110500400948000_13.8.e012457.2","doi-asserted-by":"crossref","first-page":"127ra137","DOI":"10.1126\/scitranslmed.3003689","article-title":"Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape","volume":"4","author":"Taube","year":"2012","journal-title":"Sci Transl Med"},{"key":"2025110500400948000_13.8.e012457.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2402141"},{"key":"2025110500400948000_13.8.e012457.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02498-y"},{"key":"2025110500400948000_13.8.e012457.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.010"},{"key":"2025110500400948000_13.8.e012457.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.035"},{"key":"2025110500400948000_13.8.e012457.7","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noy020"},{"key":"2025110500400948000_13.8.e012457.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1716948"},{"key":"2025110500400948000_13.8.e012457.9","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2019-000433","article-title":"Dual targeting of TGF-\u03b2 and PD-L1 via a bifunctional anti-PD-L1\/TGF-\u03b2RII agent: status of preclinical and clinical advances","volume":"8","author":"Lind","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2025110500400948000_13.8.e012457.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.10.007"},{"key":"2025110500400948000_13.8.e012457.11","doi-asserted-by":"crossref","unstructured":"Wong MK , Milhem MM , Sacco JJ , et al . RP1 combined with nivolumab in advanced anti-pd-1-failed melanoma (ignyte. 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