{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T08:15:43Z","timestamp":1778746543019,"version":"3.51.4"},"reference-count":46,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2021R1A5A2021614"],"award-info":[{"award-number":["2021R1A5A2021614"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["2022M3A9G8095334"],"award-info":[{"award-number":["2022M3A9G8095334"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Biomater Res"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:p>The immune checkpoint lymphocyte activation gene-3 (LAG-3) interacts with major histocompatibility complex class II and fibrinogen-like protein 1 (FGL-1) to suppress T cell activity, contributing to resistance against immunotherapies such as programmed death-ligand 1 (PD-L1) blockade. This study aimed to identify LAG-3-binding peptides capable of disrupting these immunosuppressive interactions. Using a phage-displayed peptide library, we identified 2 candidate peptides, LAG3pep-1 and LAG3pep-2, that preferentially bound to LAG-3-expressing cells and recombinant LAG-3 protein. A LAG-3 D1 domain-blocking antibody competitively inhibited the peptide binding to LAG-3-expressing cells, confirming target specificity. Among the 2 peptides, LAG3pep-2 demonstrated higher binding affinity and greater stability toward LAG-3. These findings were further supported by structural modeling and all-atom simulation of the LAG-3 and peptide complexes and in silico mutational analysis. Functionally, LAG3pep-2 restored interleukin-2 secretion in T cells suppressed by tumor-derived FGL-1 more effectively than LAG3pep-1. Furthermore, LAG3pep-2 synergized with a PD-L1-blocking antibody to rescue T cell cytotoxicity and cytokine production in tumor cell co-culture assays. In\u00a0vivo, systemic administration of LAG3pep-2 in combination with PD-L1 blockade significantly suppressed syngeneic tumor growth, enhanced anti-tumor immunity, and exhibited no observable systemic toxicity, outperforming either monotherapy. Collectively, these findings identify LAG3pep-2 as a peptide inhibitor of LAG-3 interaction with FGL-1 and a promising combinatorial agent to potentiate PD-L1-targeted cancer immunotherapies.<\/jats:p>","DOI":"10.34133\/bmr.0364","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:51:09Z","timestamp":1776235869000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["A Peptide Inhibitor of Lymphocyte Activation Gene-3 Interaction with Fibrinogen-like Protein 1 Synergizes with Programmed Death-Ligand 1 Blockade to Restore T Cell Activity and Inhibit Tumor Growth"],"prefix":"10.34133","volume":"30","author":[{"given":"Seok-Min","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Division of Biomedical Sciences, Graduate School, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Cell &amp; Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smriti","family":"Gurung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Division of Biomedical Sciences, Graduate School, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Cell &amp; Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Sung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Division of Biomedical Sciences, Graduate School, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Cell &amp; Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sri Murugan Poongkavithai","family":"Vadevoo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Division of Biomedical Sciences, Graduate School, Kyungpook National University, Daegu, Republic of Korea."},{"name":"Cell &amp; 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