{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T07:31:24Z","timestamp":1786347084873,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001381","name":"National Research Foundation Singapore","doi-asserted-by":"publisher","award":["CRP28\u20102022RS 0001"],"award-info":[{"award-number":["CRP28\u20102022RS 0001"]}],"id":[{"id":"10.13039\/501100001381","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["OFIRG25jan\u2010001"],"award-info":[{"award-number":["OFIRG25jan\u2010001"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Tumour immune evasion frequently involves PD\u2010L1\u2010mediated inhibition of T cell activity, limiting the efficacy of PD1\/PD\u2010L1 blockade, particularly in PD\u2010L1\u2010low or immunologically \u2018cold\u2019 tumours. To overcome this limitation, we developed a dual targeting human PD1\u2010CD137L (hPD1\u2010CD137L) fusion protein that blocks PD\u2010L1\u2013PD1 inhibitory signalling and simultaneously delivers CD137\u2010mediated T cell costimulation. The fusion protein was produced with high purity and demonstrated specific binding to PD\u2010L1\u2010expressing tumour cells and CD137\u2010positive T cells. The hPD1\u2010CD137L retained a stable multimeric structure under acidic conditions and during prolonged storage, supporting its suitability for systemic administration and activity within the tumour microenvironment. Functionally, hPD1\u2010CD137L enhanced T cell activation, as evidenced by increased NF\u2010\u03baB signalling and activation marker expression, and promoted robust tumour cell cytolysis in both 2D and 3D co\u2010culture systems. Anti\u2010tumour activity was observed across multiple tumour models with varying PD\u2010L1 expression, including nasopharyngeal carcinoma (NPC), rhabdomyosarcoma, lung carcinoma and patient\u2010derived colorectal cancer organoids. Notably, hPD1\u2010CD137L enhanced cytolysis of C666 NPC cells by patient\u2010derived tumour\u2010infiltrating lymphocytes at low effector\u2010to\u2010target ratios, and was more potent than a combination of an anti\u2010PD\u20101 antibody and a CD137 agonist. In\u00a0vivo, PBMC\u2010humanised NSG mice tolerated hPD1\u2010CD137L without significant weight loss, systemic inflammation or survival impact. Subsequent efficacy study in PBMC\u2010humanised, Rd18 rhabdomyosarcoma\u2010engrafted or C666 nasopharyngeal carcinoma\u2010engrafted NSG mice showed tumour growth suppression without overt toxicity. This study validates a human PD1\u2010CD137L fusion protein as a potent drug candidate for cancer immunotherapy.<\/jats:p>","DOI":"10.1111\/imm.70189","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T07:22:31Z","timestamp":1786346551000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A\n                    <scp>PD1<\/scp>\n                    \u2010\n                    <scp>CD137L<\/scp>\n                    Fusion Protein More Potently Enhances Anti\u2010Tumour Immune Responses Than Targeting\n                    <scp>PD<\/scp>\n                    \u2010\n                    <scp>L1<\/scp>\n                    and\n                    <scp>CD137<\/scp>\n                    Separately"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1668-7438","authenticated-orcid":false,"given":"Runze","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore  Singapore Singapore"},{"name":"NUS Immunology Programme Life Sciences Institute, National University of Singapore  Singapore Singapore"},{"name":"NUSMED Immunology Translational Research Programme National University of Singapore  Singapore Singapore"},{"name":"Integrative Sciences and Engineering Programme National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Pauline","family":"Nickles","sequence":"additional","affiliation":[{"name":"Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore  Singapore Singapore"},{"name":"NUS Immunology Programme Life Sciences Institute, National University of 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Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi Tian","family":"Png","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2010Head and Neck Surgery Singapore General Hospital  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2853-2115","authenticated-orcid":false,"given":"Beijia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore  Singapore Singapore"},{"name":"NUS Immunology Programme Life Sciences Institute, National University of Singapore  Singapore Singapore"},{"name":"NUSMED Immunology Translational Research Programme National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology Yong Loo Lin School of Medicine, National University of Singapore  Singapore Singapore"},{"name":"NUS Immunology Programme Life Sciences Institute, National University of Singapore  Singapore Singapore"},{"name":"NUSMED Immunology Translational Research Programme National University of Singapore  Singapore Singapore"},{"name":"Integrative Sciences and Engineering Programme National University of Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"NUS Immunology Programme Life Sciences Institute, National University of Singapore  Singapore Singapore"},{"name":"NUSMED Immunology Translational Research Programme National University of Singapore  Singapore Singapore"},{"name":"Department of Microbiology and Immunology Yong Loo Lin School of Medicine, National University of Singapore  Singapore 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