{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:51:20Z","timestamp":1791568280964,"version":"4.3.4"},"reference-count":152,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Rev Immunol"],"DOI":"10.1038\/s41577-026-01359-2","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T16:09:36Z","timestamp":1791562176000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LAG3 checkpoint function and its mechanism of action in therapeutic targeting"],"prefix":"10.1038","author":[{"given":"Yong","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2771-5992","authenticated-orcid":false,"given":"Dario A. A.","family":"Vignali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-0838","authenticated-orcid":false,"given":"Haopeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"1359_CR1","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1084\/jem.171.5.1393","volume":"171","author":"F Triebel","year":"1990","unstructured":"Triebel, F. et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 171, 1393\u20131405 (1990). This work marks the initial identification of LAG3, paving the way for subsequent research into its role in immunoregulation.","journal-title":"J. Exp. Med."},{"key":"1359_CR2","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41590-023-01569-z","volume":"24","author":"V Aggarwal","year":"2023","unstructured":"Aggarwal, V., Workman, C. J. & Vignali, D. A. A. LAG-3 as the third checkpoint inhibitor. Nat. Immunol. 24, 1415\u20131422 (2023).","journal-title":"Nat. Immunol."},{"key":"1359_CR3","unstructured":"US National Library of Medicine. ClinicalTrials.gov https:\/\/clinicaltrials.gov\/study\/NCT01968109 (2026)."},{"key":"1359_CR4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1056\/NEJMoa2109970","volume":"386","author":"HA Tawbi","year":"2022","unstructured":"Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24\u201334 (2022). This study demonstrates, for the first time, that dual inhibition of LAG3 and PD1 with relatlimab and nivolumab provides greater progression-free survival benefit than PD1 inhibition alone in previously untreated metastatic or unresectable melanoma, with a manageable safety profile.","journal-title":"N. Engl. J. Med."},{"key":"1359_CR5","unstructured":"US Food and Drug Administration. Drug approval package: OPDUALAG https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2022\/761234Orig1s000TOC.html (2022)."},{"key":"1359_CR6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2310866121","volume":"121","author":"JL Silberstein","year":"2024","unstructured":"Silberstein, J. L. et al. Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function. Proc. Natl Acad. Sci. USA 121, e2310866121 (2024).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR7","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ads5122","volume":"9","author":"J Petersen","year":"2024","unstructured":"Petersen, J. et al. Crystal structure of the human LAG-3\u2013HLA-DR1\u2013peptide complex. Sci. Immunol. 9, eads5122 (2024). This study visualizes the complete complex at high resolution, clarifying the precise interface between LAG3 and MHCII and aiding in the design of next-generation modulators.","journal-title":"Sci. Immunol."},{"key":"1359_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51930-5","volume":"15","author":"Q Ming","year":"2024","unstructured":"Ming, Q. et al. Structural basis for mouse LAG3 interactions with the MHC class II molecule I-A(b). Nat. Commun. 15, 7513 (2024).","journal-title":"Nat. Commun."},{"key":"1359_CR9","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1038\/s41590-022-01238-7","volume":"23","author":"Q Ming","year":"2022","unstructured":"Ming, Q. et al. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat. Immunol. 23, 1031\u20131041 (2022). This study resolves the structure of the LAG3 extracellular domain, providing the structural basis for understanding antibody binding and ligand interaction surfaces.","journal-title":"Nat. Immunol."},{"key":"1359_CR10","doi-asserted-by":"publisher","first-page":"7","DOI":"10.4049\/jimmunol.2300673","volume":"213","author":"K Adam","year":"2024","unstructured":"Adam, K. et al. Cutting edge: LAG3 dimerization is required for TCR\/CD3 interaction and inhibition of antitumor immunity. J. Immunol. 213, 7\u201313 (2024). Together with Silberstein et al. (2024), this study demonstrates that disrupting the dimerization of LAG3, which is crucial for its function, simultaneously blocks ligand binding, revealing a new therapeutic strategy.","journal-title":"J. Immunol."},{"key":"1359_CR11","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/sj.emboj.7601520","volume":"26","author":"N Li","year":"2007","unstructured":"Li, N. et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. EMBO J. 26, 494\u2013504 (2007). This study identifies metalloproteases (ADAM10 and ADAM17) as regulators of LAG3 shedding, elucidating the mechanism controlling the receptor\u2019s surface density and the generation of sLAG3.","journal-title":"EMBO J."},{"key":"1359_CR12","doi-asserted-by":"publisher","first-page":"eabc2728","DOI":"10.1126\/sciimmunol.abc2728","volume":"5","author":"LP Andrews","year":"2020","unstructured":"Andrews, L. P. et al. Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Sci. Immunol. 5, eabc2728 (2020).","journal-title":"Sci. Immunol."},{"key":"1359_CR13","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.cell.2018.11.010","volume":"176","author":"J Wang","year":"2019","unstructured":"Wang, J. et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334\u2013347 (2019). This study identifies FGL1 as another functional ligand, expanding the interaction network of LAG3 beyond MHCII.","journal-title":"Cell"},{"key":"1359_CR14","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/s41590-022-01176-4","volume":"23","author":"C Guy","year":"2022","unstructured":"Guy, C. et al. LAG3 associates with TCR\u2013CD3 complexes and suppresses signaling by driving co-receptor\u2013Lck dissociation. Nat. Immunol. 23, 757\u2013767 (2022). This research highlights a non-canonical signalling mechanism through which the EP motif drives LAG3 function even in the absence of canonical ligand binding.","journal-title":"Nat. Immunol."},{"key":"1359_CR15","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1158\/2326-6066.CIR-14-0150","volume":"3","author":"T Kouo","year":"2015","unstructured":"Kouo, T. et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol. Res. 3, 412\u2013423 (2015).","journal-title":"Cancer Immunol. Res."},{"key":"1359_CR16","doi-asserted-by":"publisher","first-page":"3418","DOI":"10.1158\/0008-5472.CAN-13-2690","volume":"74","author":"F Xu","year":"2014","unstructured":"Xu, F. et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 74, 3418\u20133428 (2014).","journal-title":"Cancer Res."},{"key":"1359_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49016-3","volume":"15","author":"X Mao","year":"2024","unstructured":"Mao, X. et al. Aplp1 interacts with Lag3 to facilitate transmission of pathologic \u03b1-synuclein. Nat. Commun. 15, 4663 (2024).","journal-title":"Nat. Commun."},{"key":"1359_CR18","doi-asserted-by":"publisher","first-page":"aah3374","DOI":"10.1126\/science.aah3374","volume":"353","author":"X Mao","year":"2016","unstructured":"Mao, X. et al. Pathological \u03b1-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).","journal-title":"Science"},{"key":"1359_CR19","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1084\/jem.176.2.327","volume":"176","author":"E Baixeras","year":"1992","unstructured":"Baixeras, E. et al. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 176, 327\u2013337 (1992). This pivotal discovery established MHCII as the canonical binding partner, linking LAG3 directly to T cell activation pathways.","journal-title":"J. Exp. Med."},{"key":"1359_CR20","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1111\/imr.12519","volume":"276","author":"LP Andrews","year":"2017","unstructured":"Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80\u201396 (2017).","journal-title":"Immunol. Rev."},{"key":"1359_CR21","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.trecan.2024.10.009","volume":"11","author":"K Adam","year":"2025","unstructured":"Adam, K., Butler, S. C., Workman, C. J. & Vignali, D. A. A. Advances in LAG3 cancer immunotherapeutics. Trends Cancer 11, 37\u201348 (2025).","journal-title":"Trends Cancer"},{"key":"1359_CR22","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.tips.2025.05.008","volume":"46","author":"J Wang","year":"2025","unstructured":"Wang, J., Klein, C., Cochran, J. R., Sockolosky, J. & Lippow, S. M. Exploring new frontiers in LAG-3 biology and therapeutics. Trends Pharmacol. Sci. 46, 638\u2013652 (2025).","journal-title":"Trends Pharmacol. Sci."},{"key":"1359_CR23","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.immuni.2022.03.013","volume":"55","author":"T Maruhashi","year":"2022","unstructured":"Maruhashi, T. et al. Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity. Immunity 55, 912\u2013924.e8 (2022).","journal-title":"Immunity"},{"key":"1359_CR24","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1158\/0008-5472.CAN-11-1620","volume":"72","author":"SR Woo","year":"2012","unstructured":"Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917\u2013927 (2012). This study demonstrates that co-blockade of LAG3 and PD1 is far more effective than single molecule blockade, providing the rationale for modern combination immunotherapies.","journal-title":"Cancer Res."},{"key":"1359_CR25","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41590-018-0217-9","volume":"19","author":"T Maruhashi","year":"2018","unstructured":"Maruhashi, T. et al. LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat. Immunol. 19, 1415\u20131426 (2018). This study refines our understanding of ligand specificity, showing that LAG3 preferentially recognizes stable pMHCII complexes rather than MHCII alone.","journal-title":"Nat. Immunol."},{"key":"1359_CR26","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.4049\/jimmunol.1100714","volume":"187","author":"M Bettini","year":"2011","unstructured":"Bettini, M. et al. Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3. J. Immunol. 187, 3493\u20133498 (2011).","journal-title":"J. Immunol."},{"key":"1359_CR27","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1084\/jem.20100466","volume":"208","author":"T Okazaki","year":"2011","unstructured":"Okazaki, T. et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J. Exp. Med. 208, 395\u2013407 (2011). The study reveals that LAG3 cooperates with PD1 to prevent spontaneous autoimmune disease in mice.","journal-title":"J. Exp. Med."},{"key":"1359_CR28","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1084\/jem.181.2.765","volume":"181","author":"CH Chang","year":"1995","unstructured":"Chang, C. H. & Flavell, R. A. Class II transactivator regulates the expression of multiple genes involved in antigen presentation. J. Exp. Med. 181, 765\u2013767 (1995).","journal-title":"J. Exp. Med."},{"key":"1359_CR29","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adg2610","volume":"16","author":"K Aigner-Radakovics","year":"2023","unstructured":"Aigner-Radakovics, K. et al. The ligand-dependent suppression of TCR signaling by the immune checkpoint receptor LAG3 depends on the cytoplasmic RRFSALE motif. Sci. Signal. 16, eadg2610 (2023).","journal-title":"Sci. Signal."},{"key":"1359_CR30","doi-asserted-by":"publisher","first-page":"5173","DOI":"10.4049\/jimmunol.1002050","volume":"186","author":"P Hemon","year":"2011","unstructured":"Hemon, P. et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J. Immunol. 186, 5173\u20135183 (2011).","journal-title":"J. Immunol."},{"key":"1359_CR31","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1002\/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A","volume":"32","author":"CJ Workman","year":"2002","unstructured":"Workman, C. J., Rice, D. S., Dugger, K. J., Kurschner, C. & Vignali, D. A. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur. J. Immunol. 32, 2255\u20132263 (2002).","journal-title":"Eur. J. Immunol."},{"key":"1359_CR32","doi-asserted-by":"publisher","first-page":"767868","DOI":"10.3389\/fimmu.2021.767868","volume":"12","author":"WW Lin","year":"2021","unstructured":"Lin, W. W. et al. Fibrinogen-like protein 1 serves as an anti-inflammatory agent for collagen-induced arthritis therapy in mice. Front. Immunol. 12, 767868 (2021).","journal-title":"Front. Immunol."},{"key":"1359_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-024-00601-0","volume":"12","author":"J Chen","year":"2024","unstructured":"Chen, J., Wu, L. & Li, Y. FGL1 and FGL2: emerging regulators of liver health and disease. Biomark Res. 12, 53 (2024).","journal-title":"Biomark Res."},{"key":"1359_CR34","doi-asserted-by":"publisher","DOI":"10.1172\/JCI164528","volume":"133","author":"M Lin","year":"2023","unstructured":"Lin, M. et al. Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma. J. Clin. Invest. 133, e164528 (2023).","journal-title":"J. Clin. Invest."},{"key":"1359_CR35","doi-asserted-by":"publisher","first-page":"113362","DOI":"10.1016\/j.celrep.2023.113362","volume":"42","author":"T Tian","year":"2023","unstructured":"Tian, T. et al. FBXO38 mediates FGL1 ubiquitination and degradation to enhance cancer immunity and suppress inflammation. Cell Rep. 42, 113362 (2023).","journal-title":"Cell Rep."},{"key":"1359_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42332-0","volume":"14","author":"JJ Li","year":"2023","unstructured":"Li, J. J. et al. The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer. Nat. Commun. 14, 6690 (2023).","journal-title":"Nat. Commun."},{"key":"1359_CR37","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.173215","volume":"9","author":"F Xi","year":"2024","unstructured":"Xi, F. et al. Hepatocyte-derived FGL1 accelerates liver metastasis and tumor growth by inhibiting CD8+ T and NK cells. JCI Insight 9, e173215 (2024).","journal-title":"JCI Insight"},{"key":"1359_CR38","doi-asserted-by":"publisher","first-page":"2354","DOI":"10.1016\/j.cell.2025.02.014","volume":"188","author":"Y Jiang","year":"2025","unstructured":"Jiang, Y. et al. Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs. Cell 188, 2354\u20132371.e18 (2025). This study uncovers a post-translational regulatory mechanism, suggesting that ubiquitination is a \u2018switch\u2019 that activates the suppressive capability of LAG3.","journal-title":"Cell"},{"key":"1359_CR39","doi-asserted-by":"publisher","first-page":"4355","DOI":"10.1016\/j.cell.2024.07.016","volume":"187","author":"LP Andrews","year":"2024","unstructured":"Andrews, L. P. et al. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-\u03b3-dependent anti-tumor immunity. Cell 187, 4355\u20134372.e22 (2024).","journal-title":"Cell"},{"key":"1359_CR40","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1038\/s41375-021-01301-6","volume":"36","author":"J Bae","year":"2022","unstructured":"Bae, J. et al. Targeting LAG3\/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma. Leukemia 36, 138\u2013154 (2022).","journal-title":"Leukemia"},{"key":"1359_CR41","doi-asserted-by":"publisher","first-page":"101482","DOI":"10.1016\/j.jhepr.2025.101482","volume":"7","author":"S Martinez-Lopez","year":"2025","unstructured":"Martinez-Lopez, S. et al. LSECtin attenuates hepatic TH17 expansion in a murine model of cirrhosis and signals through the LAG-3 receptor. JHEP Rep. 7, 101482 (2025).","journal-title":"JHEP Rep."},{"key":"1359_CR42","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114745","volume":"13","author":"M Emmenegger","year":"2021","unstructured":"Emmenegger, M. et al. LAG3 is not expressed in human and murine neurons and does not modulate \u03b1-synucleinopathies. EMBO Mol. Med. 13, e14745 (2021).","journal-title":"EMBO Mol. Med."},{"key":"1359_CR43","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aay4458","volume":"6","author":"M Marasco","year":"2020","unstructured":"Marasco, M. et al. Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci. Adv. 6, eaay4458 (2020).","journal-title":"Sci. Adv."},{"key":"1359_CR44","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.immuni.2024.01.010","volume":"57","author":"N Joller","year":"2024","unstructured":"Joller, N., Anderson, A. C. & Kuchroo, V. K. LAG-3, TIM-3, and TIGIT: distinct functions in immune regulation. Immunity 57, 206\u2013222 (2024).","journal-title":"Immunity"},{"key":"1359_CR45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107141118","volume":"118","author":"K Shimizu","year":"2021","unstructured":"Shimizu, K. et al. PD-1 preferentially inhibits the activation of low-affinity T cells. Proc. Natl Acad. Sci. USA 118, e2107141118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR46","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1126\/science.aaf1292","volume":"355","author":"E Hui","year":"2017","unstructured":"Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428\u20131433 (2017).","journal-title":"Science"},{"key":"1359_CR47","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1084\/jem.20112741","volume":"209","author":"T Yokosuka","year":"2012","unstructured":"Yokosuka, T. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209, 1201\u20131217 (2012).","journal-title":"J. Exp. Med."},{"key":"1359_CR48","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001014","volume":"8","author":"T Maruhashi","year":"2020","unstructured":"Maruhashi, T., Sugiura, D., Okazaki, I. M. & Okazaki, T. LAG-3: from molecular functions to clinical applications. J. Immunother. Cancer 8, e001014 (2020).","journal-title":"J. Immunother. Cancer"},{"key":"1359_CR49","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1038\/s41586-020-2851-2","volume":"586","author":"RA Fernandes","year":"2020","unstructured":"Fernandes, R. A. et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature 586, 779\u2013784 (2020).","journal-title":"Nature"},{"key":"1359_CR50","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1038\/s41590-022-01196-0","volume":"23","author":"C Hivroz","year":"2022","unstructured":"Hivroz, C. LAG3 disrupts the TCR signal by local acidification. Nat. Immunol. 23, 649\u2013651 (2022).","journal-title":"Nat. Immunol."},{"key":"1359_CR51","doi-asserted-by":"publisher","first-page":"32878","DOI":"10.1074\/jbc.273.49.32878","volume":"273","author":"RS Lin","year":"1998","unstructured":"Lin, R. S., Rodriguez, C., Veillette, A. & Lodish, H. F. Zinc is essential for binding of p56lck to CD4 and CD8\u03b1. J. Biol. Chem. 273, 32878\u201332882 (1998).","journal-title":"J. Biol. Chem."},{"key":"1359_CR52","doi-asserted-by":"publisher","first-page":"18729","DOI":"10.1074\/jbc.273.30.18729","volume":"273","author":"M Huse","year":"1998","unstructured":"Huse, M., Eck, M. J. & Harrison, S. C. A Zn2+ ion links the cytoplasmic tail of CD4 and the N-terminal region of Lck. J. Biol. Chem. 273, 18729\u201318733 (1998).","journal-title":"J. Biol. Chem."},{"key":"1359_CR53","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adt3018","volume":"18","author":"PK Van Dyck","year":"2025","unstructured":"Van Dyck, P. K. et al. Ionizable networks mediate pH-dependent allostery in the SH2 domain-containing signaling proteins SHP2 and SRC. Sci. Signal. 18, eadt3018 (2025).","journal-title":"Sci. Signal."},{"key":"1359_CR54","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1016\/j.immuni.2023.11.010","volume":"56","author":"YL Tsai","year":"2023","unstructured":"Tsai, Y. L. et al. TCR signaling promotes formation of an STS1\u2013Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments. Immunity 56, 2682\u20132698.e9 (2023).","journal-title":"Immunity"},{"key":"1359_CR55","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.celrep.2019.03.004","volume":"27","author":"DM Previte","year":"2019","unstructured":"Previte, D. M. et al. Lymphocyte activation gene-3 maintains mitochondrial and metabolic quiescence in naive CD4+ T cells. Cell Rep. 27, 129\u2013141.e4 (2019).","journal-title":"Cell Rep."},{"key":"1359_CR56","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1016\/j.immuni.2024.08.008","volume":"57","author":"D Kim","year":"2024","unstructured":"Kim, D. et al. Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming. Immunity 57, 2634\u20132650.e5 (2024).","journal-title":"Immunity"},{"key":"1359_CR57","doi-asserted-by":"publisher","first-page":"4025","DOI":"10.1016\/j.cell.2025.06.004","volume":"188","author":"J Du","year":"2025","unstructured":"Du, J. et al. Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity. Cell 188, 4025\u20134042.e20 (2025). This study establishes that LAG3 must be positioned close to the TCR complex to exert its inhibitory effect, emphasizing the importance of membrane topology.","journal-title":"Cell"},{"key":"1359_CR58","doi-asserted-by":"publisher","first-page":"6017","DOI":"10.1074\/jbc.RA119.007455","volume":"294","author":"TK Maeda","year":"2019","unstructured":"Maeda, T. K., Sugiura, D., Okazaki, I. M., Maruhashi, T. & Okazaki, T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J. Biol. Chem. 294, 6017\u20136026 (2019). This work discovers the FSALE motif, offering further resolution on the intracellular requirements for LAG3 inhibitory function.","journal-title":"J. Biol. Chem."},{"key":"1359_CR59","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.cell.2008.09.044","volume":"135","author":"C Xu","year":"2008","unstructured":"Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3\u03b5 cytoplasmic tyrosine-based motif. Cell 135, 702\u2013713 (2008).","journal-title":"Cell"},{"key":"1359_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9552","volume":"6","author":"X Chen","year":"2015","unstructured":"Chen, X. et al. Acidic phospholipids govern the enhanced activation of IgG-B cell receptor. Nat. Commun. 6, 8552 (2015).","journal-title":"Nat. Commun."},{"key":"1359_CR61","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1038\/nsmb.3489","volume":"24","author":"W Yang","year":"2017","unstructured":"Yang, W. et al. Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nat. Struct. Mol. Biol. 24, 1081\u20131092 (2017).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"1359_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25416-7","volume":"12","author":"M Wen","year":"2021","unstructured":"Wen, M. et al. PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain. Nat. Commun. 12, 5106 (2021).","journal-title":"Nat. Commun."},{"key":"1359_CR63","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1182\/blood.2022017819","volume":"141","author":"B Mo\u00ebs","year":"2023","unstructured":"Mo\u00ebs, B. et al. INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors. Blood 141, 1708\u20131717 (2023).","journal-title":"Blood"},{"key":"1359_CR64","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1038\/emboj.2010.10","volume":"29","author":"H Wang","year":"2010","unstructured":"Wang, H. et al. Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development. EMBO J. 29, 1285\u20131298 (2010).","journal-title":"EMBO J."},{"key":"1359_CR65","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1038\/s41586-018-0756-0","volume":"564","author":"X Meng","year":"2018","unstructured":"Meng, X. et al. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature 564, 130\u2013135 (2018).","journal-title":"Nature"},{"key":"1359_CR66","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/ncb983","volume":"5","author":"K Haglund","year":"2003","unstructured":"Haglund, K. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat. Cell Biol. 5, 461\u2013466 (2003).","journal-title":"Nat. Cell Biol."},{"key":"1359_CR67","doi-asserted-by":"publisher","first-page":"5392","DOI":"10.4049\/jimmunol.169.10.5392","volume":"169","author":"CJ Workman","year":"2002","unstructured":"Workman, C. J., Dugger, K. J. & Vignali, D. A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 169, 5392\u20135395 (2002). This study maps the highly conserved KIEELE motif in the cytoplasmic tail, revealing a key structural element essential for LAG3 downstream inhibitory signalling.","journal-title":"J. Immunol."},{"key":"1359_CR68","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1016\/j.cell.2025.03.030","volume":"188","author":"Y Zhao","year":"2025","unstructured":"Zhao, Y. & Wucherpfennig, K. W. Unlocking LAG3: ubiquitin\u2019s unexpected role. Cell 188, 2307\u20132309 (2025).","journal-title":"Cell"},{"key":"1359_CR69","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nsmb.2231","volume":"19","author":"H Dou","year":"2012","unstructured":"Dou, H. et al. Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nat. Struct. Mol. Biol. 19, 184\u2013192 (2012).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"1359_CR70","doi-asserted-by":"publisher","first-page":"20579","DOI":"10.1073\/pnas.1110712108","volume":"108","author":"Y Kobashigawa","year":"2011","unstructured":"Kobashigawa, Y. et al. Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b. Proc. Natl Acad. Sci. USA 108, 20579\u201320584 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR71","doi-asserted-by":"publisher","first-page":"28017","DOI":"10.1074\/jbc.M404114200","volume":"279","author":"CK Kassenbrock","year":"2004","unstructured":"Kassenbrock, C. K. & Anderson, S. M. Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations. J. Biol. Chem. 279, 28017\u201328027 (2004).","journal-title":"J. Biol. Chem."},{"key":"1359_CR72","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201905085","volume":"219","author":"X Xu","year":"2020","unstructured":"Xu, X. et al. PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. J. Cell Biol. 219, e201905085 (2020).","journal-title":"J. Cell Biol."},{"key":"1359_CR73","doi-asserted-by":"publisher","first-page":"13866","DOI":"10.1073\/pnas.231486598","volume":"98","author":"T Okazaki","year":"2001","unstructured":"Okazaki, T., Maeda, A., Nishimura, H., Kurosaki, T. & Honjo, T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl Acad. Sci. USA 98, 13866\u201313871 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR74","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2217301120","volume":"120","author":"H Chen","year":"2023","unstructured":"Chen, H. et al. Self-programmed dynamics of T cell receptor condensation. Proc. Natl Acad. Sci. USA 120, e2217301120 (2023).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR75","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41422-025-01168-7","volume":"36","author":"GJ Fiala","year":"2026","unstructured":"Fiala, G. J. & Schamel, W. W. Sabotaging TCR signaling\u2014LAG3 interferes with the CD3\u03b5\u2013LCK interaction. Cell Res. 36, 3\u20134 (2026).","journal-title":"Cell Res."},{"key":"1359_CR76","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1002\/eji.202048753","volume":"51","author":"BJ MacLachlan","year":"2021","unstructured":"MacLachlan, B. J. et al. Molecular characterization of HLA class II binding to the LAG-3 T cell co-inhibitory receptor. Eur. J. Immunol. 51, 331\u2013341 (2021).","journal-title":"Eur. J. Immunol."},{"key":"1359_CR77","doi-asserted-by":"publisher","first-page":"15960","DOI":"10.1073\/pnas.1109438108","volume":"108","author":"XX Wang","year":"2011","unstructured":"Wang, X. X. et al. Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4\u2013HLA-DR1 complex. Proc. Natl Acad. Sci. USA 108, 15960\u201315965 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR78","doi-asserted-by":"publisher","first-page":"6806","DOI":"10.4049\/jimmunol.173.11.6806","volume":"173","author":"N Li","year":"2004","unstructured":"Li, N., Workman, C. J., Martin, S. M. & Vignali, D. A. Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J. Immunol. 173, 6806\u20136812 (2004).","journal-title":"J. Immunol."},{"key":"1359_CR79","doi-asserted-by":"publisher","first-page":"2718","DOI":"10.1002\/eji.1830250949","volume":"25","author":"B Huard","year":"1995","unstructured":"Huard, B., Prigent, P., Tournier, M., Bruniquel, D. & Triebel, F. CD4\/major histocompatibility complex class II interaction analyzed with CD4\u2013 and lymphocyte activation gene-3 (LAG-3)\u2013Ig fusion proteins. Eur. J. Immunol. 25, 2718\u20132721 (1995).","journal-title":"Eur. J. Immunol."},{"key":"1359_CR80","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1016\/j.immuni.2025.06.011","volume":"58","author":"T Deng","year":"2025","unstructured":"Deng, T. et al. CINTER-seq: chemical profiling reveals interaction-dependent cell landscapes and gene signatures in vivo. Immunity 58, 2336\u20132352.e12 (2025).","journal-title":"Immunity"},{"key":"1359_CR81","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1093\/jimmun\/vkaf120","volume":"214","author":"Z Wang","year":"2025","unstructured":"Wang, Z. et al. LAG3\u2013MHCII interaction induces a tight cell-cell interface at the immunological synapse. J. Immunol. 214, 2256\u20132269 (2025).","journal-title":"J. Immunol."},{"key":"1359_CR82","doi-asserted-by":"publisher","first-page":"114655","DOI":"10.1016\/j.celrep.2024.114655","volume":"43","author":"E Wakamatsu","year":"2024","unstructured":"Wakamatsu, E. et al. Indirect suppression of CD4 T cell activation through LAG-3-mediated trans-endocytosis of MHC class II. Cell Rep. 43, 114655 (2024).","journal-title":"Cell Rep."},{"key":"1359_CR83","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1002\/eji.200323382","volume":"33","author":"CJ Workman","year":"2003","unstructured":"Workman, C. J. & Vignali, D. A. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur. J. Immunol. 33, 970\u2013979 (2003).","journal-title":"Eur. J. Immunol."},{"key":"1359_CR84","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1146\/annurev-immunol-090222-110914","volume":"42","author":"A Baessler","year":"2024","unstructured":"Baessler, A. & Vignali, D. A. A. T cell exhaustion. Annu. Rev. Immunol. 42, 179\u2013206 (2024).","journal-title":"Annu. Rev. Immunol."},{"key":"1359_CR85","doi-asserted-by":"publisher","first-page":"12410","DOI":"10.1073\/pnas.1905675116","volume":"116","author":"H Seo","year":"2019","unstructured":"Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl Acad. Sci. USA 116, 12410\u201312415 (2019).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR86","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","volume":"571","author":"AC Scott","year":"2019","unstructured":"Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270\u2013274 (2019).","journal-title":"Nature"},{"key":"1359_CR87","doi-asserted-by":"publisher","first-page":"4336","DOI":"10.1016\/j.cell.2024.07.018","volume":"187","author":"SF Ngiow","year":"2024","unstructured":"Ngiow, S. F. et al. LAG-3 sustains TOX expression and regulates the CD94\/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 187, 4336\u20134354.e19 (2024).","journal-title":"Cell"},{"key":"1359_CR88","doi-asserted-by":"publisher","first-page":"688","DOI":"10.4049\/jimmunol.174.2.688","volume":"174","author":"CJ Workman","year":"2005","unstructured":"Workman, C. J. & Vignali, D. A. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J. Immunol. 174, 688\u2013695 (2005).","journal-title":"J. Immunol."},{"key":"1359_CR89","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.immuni.2004.08.010","volume":"21","author":"CT Huang","year":"2004","unstructured":"Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503\u2013513 (2004).","journal-title":"Immunity"},{"key":"1359_CR90","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.4049\/jimmunol.172.9.5450","volume":"172","author":"CJ Workman","year":"2004","unstructured":"Workman, C. J. et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 172, 5450\u20135455 (2004). This study provides the first definitive in vivo evidence that LAG3 acts as an immune checkpoint to limit T cell proliferation, validating it as a potential therapeutic target.","journal-title":"J. Immunol."},{"key":"1359_CR91","doi-asserted-by":"publisher","first-page":"3383","DOI":"10.1172\/JCI31184","volume":"117","author":"JF Grosso","year":"2007","unstructured":"Grosso, J. F. et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 117, 3383\u20133392 (2007).","journal-title":"J. Clin. Invest."},{"key":"1359_CR92","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1038\/s41590-022-01210-5","volume":"23","author":"S Grebinoski","year":"2022","unstructured":"Grebinoski, S. et al. Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3. Nat. Immunol. 23, 868\u2013877 (2022).","journal-title":"Nat. Immunol."},{"key":"1359_CR93","doi-asserted-by":"publisher","DOI":"10.1172\/JCI172988","volume":"135","author":"M Nicosia","year":"2025","unstructured":"Nicosia, M. et al. LAG3 regulates antibody responses in a murine model of kidney transplantation. J. Clin. Invest. 135, e172988 (2025).","journal-title":"J. Clin. Invest."},{"key":"1359_CR94","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/mi.2015.45","volume":"9","author":"JS Do","year":"2016","unstructured":"Do, J. S. et al. An IL-27\/Lag3 axis enhances Foxp3+ regulatory T cell-suppressive function and therapeutic efficacy. Mucosal Immunol. 9, 137\u2013145 (2016).","journal-title":"Mucosal Immunol."},{"key":"1359_CR95","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.immuni.2018.07.007","volume":"49","author":"D Bauche","year":"2018","unstructured":"Bauche, D. et al. LAG3+ regulatory T cells restrain interleukin-23-producing CX3CR1+ gut-resident macrophages during group 3 innate lymphoid cell-driven colitis. Immunity 49, 342\u2013352.e5 (2018).","journal-title":"Immunity"},{"key":"1359_CR96","doi-asserted-by":"publisher","first-page":"eaah4569","DOI":"10.1126\/sciimmunol.aah4569","volume":"2","author":"Q Zhang","year":"2017","unstructured":"Zhang, Q. et al. LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci. Immunol. 2, eaah4569 (2017).","journal-title":"Sci. Immunol."},{"key":"1359_CR97","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486\u2013499 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"1359_CR98","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","volume":"19","author":"CU Blank","year":"2019","unstructured":"Blank, C. U. et al. Defining \u2018T cell exhaustion\u2019. Nat. Rev. Immunol. 19, 665\u2013674 (2019).","journal-title":"Nat. Rev. Immunol."},{"key":"1359_CR99","doi-asserted-by":"publisher","first-page":"6659","DOI":"10.4049\/jimmunol.0804211","volume":"182","author":"JF Grosso","year":"2009","unstructured":"Grosso, J. F. et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J. Immunol. 182, 6659\u20136669 (2009).","journal-title":"J. Immunol."},{"key":"1359_CR100","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ni.1679","volume":"10","author":"SD Blackburn","year":"2009","unstructured":"Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29\u201337 (2009).","journal-title":"Nat. Immunol."},{"key":"1359_CR101","doi-asserted-by":"publisher","first-page":"4373","DOI":"10.1016\/j.cell.2024.06.036","volume":"187","author":"AR Cillo","year":"2024","unstructured":"Cillo, A. R. et al. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell 187, 4373\u20134388.e15 (2024).","journal-title":"Cell"},{"key":"1359_CR102","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","volume":"571","author":"O Khan","year":"2019","unstructured":"Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211\u2013218 (2019).","journal-title":"Nature"},{"key":"1359_CR103","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/s41590-020-00817-w","volume":"22","author":"N Hensel","year":"2021","unstructured":"Hensel, N. et al. Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection. Nat. Immunol. 22, 229\u2013239 (2021).","journal-title":"Nat. Immunol."},{"key":"1359_CR104","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1038\/s41590-021-00979-1","volume":"22","author":"KB Yates","year":"2021","unstructured":"Yates, K. B. et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat. Immunol. 22, 1020\u20131029 (2021).","journal-title":"Nat. Immunol."},{"key":"1359_CR105","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1038\/s41590-021-00975-5","volume":"22","author":"MS Abdel-Hakeem","year":"2021","unstructured":"Abdel-Hakeem, M. S. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat. Immunol. 22, 1008\u20131019 (2021).","journal-title":"Nat. Immunol."},{"key":"1359_CR106","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1126\/science.aaf2807","volume":"354","author":"KE Pauken","year":"2016","unstructured":"Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160\u20131165 (2016).","journal-title":"Science"},{"key":"1359_CR107","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/s41586-022-05626-9","volume":"614","author":"AG Soerens","year":"2023","unstructured":"Soerens, A. G. et al. Functional T cells are capable of supernumerary cell division and longevity. Nature 614, 762\u2013766 (2023).","journal-title":"Nature"},{"key":"1359_CR108","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ado3032","volume":"10","author":"YJ Huang","year":"2025","unstructured":"Huang, Y. J. et al. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci. Immunol. 10, eado3032 (2025).","journal-title":"Sci. Immunol."},{"key":"1359_CR109","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","volume":"571","author":"F Alfei","year":"2019","unstructured":"Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265\u2013269 (2019).","journal-title":"Nature"},{"key":"1359_CR110","doi-asserted-by":"publisher","first-page":"5744","DOI":"10.1073\/pnas.94.11.5744","volume":"94","author":"B Huard","year":"1997","unstructured":"Huard, B. et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc. Natl Acad. Sci. USA 94, 5744\u20135749 (1997).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR111","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.4049\/jimmunol.2200309","volume":"209","author":"P Agnihotri","year":"2022","unstructured":"Agnihotri, P. et al. Epitope mapping of therapeutic antibodies targeting human LAG3. J. Immunol. 209, 1586\u20131594 (2022).","journal-title":"J. Immunol."},{"key":"1359_CR112","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1158\/2326-6066.CIR-22-0057","volume":"10","author":"K Thudium","year":"2022","unstructured":"Thudium, K. et al. Preclinical characterization of relatlimab, a human LAG-3-blocking antibody, alone or in combination with nivolumab. Cancer Immunol. Res. 10, 1175\u20131189 (2022).","journal-title":"Cancer Immunol. Res."},{"key":"1359_CR113","doi-asserted-by":"publisher","DOI":"10.1111\/imr.70002","volume":"330","author":"VC Luca","year":"2025","unstructured":"Luca, V. C. LAG time in the era of immunotherapy-new molecular insights into the immunosuppression mechanism of lymphocyte activation gene-3. Immunol. Rev. 330, e70002 (2025).","journal-title":"Immunol. Rev."},{"key":"1359_CR114","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003776","volume":"10","author":"P Sch\u00f6ffski","year":"2022","unstructured":"Sch\u00f6ffski, P. et al. Phase I\/II study of the LAG-3 inhibitor ieramilimab (LAG525) \u00b1 anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies. J. ImmunoTher. Cancer. 10, e003776 (2022).","journal-title":"J. ImmunoTher. Cancer."},{"key":"1359_CR115","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/sj.gene.6364171","volume":"6","author":"Z Zhang","year":"2005","unstructured":"Zhang, Z. et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 6, 145\u2013152 (2005).","journal-title":"Genes Immun."},{"key":"1359_CR116","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50007-7","volume":"15","author":"S Saevarsdottir","year":"2024","unstructured":"Saevarsdottir, S. et al. Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease. Nat. Commun. 15, 5748 (2024).","journal-title":"Nat. Commun."},{"key":"1359_CR117","doi-asserted-by":"publisher","first-page":"810","DOI":"10.4049\/jimmunol.1900823","volume":"204","author":"M Angin","year":"2020","unstructured":"Angin, M., Brignone, C. & Triebel, F. A LAG-3-specific agonist antibody for the treatment of T cell-induced autoimmune diseases. J. Immunol. 204, 810\u2013818 (2020).","journal-title":"J. Immunol."},{"key":"1359_CR118","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1056\/NEJMoa2209856","volume":"388","author":"J Tuttle","year":"2023","unstructured":"Tuttle, J. et al. A phase 2 trial of peresolimab for adults with rheumatoid arthritis. N. Engl. J. Med. 388, 1853\u20131862 (2023).","journal-title":"N. Engl. J. Med."},{"key":"1359_CR119","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.add4947","volume":"8","author":"K Suzuki","year":"2023","unstructured":"Suzuki, K. et al. Anti-PD-1 antibodies recognizing the membrane-proximal region are PD-1 agonists that can down-regulate inflammatory diseases. Sci. Immunol. 8, eadd4947 (2023).","journal-title":"Sci. Immunol."},{"key":"1359_CR120","doi-asserted-by":"publisher","first-page":"117141","DOI":"10.1016\/j.ejmech.2024.117141","volume":"283","author":"B Cheng","year":"2025","unstructured":"Cheng, B. et al. Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020\u20132024). Eur. J. Med. Chem. 283, 117141 (2025).","journal-title":"Eur. J. Med. Chem."},{"key":"1359_CR121","doi-asserted-by":"publisher","first-page":"17473","DOI":"10.1021\/acs.jmedchem.5c00995","volume":"68","author":"SA Abdel-Rahman","year":"2025","unstructured":"Abdel-Rahman, S. A., Calvo-Barreiro, L., Vazquez, N. G., Nada, H. & Gabr, M. T. Discovery and optimization of LAG-3-targeted small molecules via DNA-encoded chemical library (DEL) screening for cancer immunotherapy. J. Med. Chem. 68, 17473\u201317484 (2025).","journal-title":"J. Med. Chem."},{"key":"1359_CR122","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1021\/acsmedchemlett.3c00054","volume":"14","author":"SA Abdel-Rahman","year":"2023","unstructured":"Abdel-Rahman, S. A., Rehman, A. U. & Gabr, M. T. Discovery of first-in-class small molecule inhibitors of lymphocyte activation gene 3 (LAG-3). ACS Med. Chem. Lett. 14, 629\u2013635 (2023).","journal-title":"ACS Med. Chem. Lett."},{"key":"1359_CR123","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.apsb.2020.01.005","volume":"10","author":"W Zhai","year":"2020","unstructured":"Zhai, W. et al. A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigen-specific CD8+ T cell responses. Acta Pharm. Sin. B 10, 1047\u20131060 (2020).","journal-title":"Acta Pharm. Sin. B"},{"key":"1359_CR124","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1016\/j.apsb.2023.12.011","volume":"14","author":"Y Qian","year":"2024","unstructured":"Qian, Y. et al. Development of LAG-3\/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy. Acta Pharm. Sin. B 14, 1150\u20131165 (2024).","journal-title":"Acta Pharm. Sin. B"},{"key":"1359_CR125","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1158\/1538-7445.AM2023-462","volume":"83","author":"M Chinnapattu","year":"2023","unstructured":"Chinnapattu, M. et al. Abstract 462: a novel and potent Cblb inhibitor demonstrates robust immunological profile and anti-tumor efficacy. Cancer Res. 83, 462 (2023).","journal-title":"Cancer Res."},{"key":"1359_CR126","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1158\/1538-7445.AM2021-1595","volume":"81","author":"R Rountree","year":"2021","unstructured":"Rountree, R. et al. Abstract 1595: small molecule inhibition of the ubiquitin ligase CBL-B results in potent T and NK cell mediated anti-tumor response. Cancer Res. 81, 1595 (2021).","journal-title":"Cancer Res."},{"key":"1359_CR127","doi-asserted-by":"publisher","first-page":"117677","DOI":"10.1016\/j.bmc.2024.117677","volume":"102","author":"X Hu","year":"2024","unstructured":"Hu, X., Li, E., Zhou, Y., You, Q. & Jiang, Z. Casitas B cell lymphoma-b (Cbl-b): a new therapeutic avenue for small-molecule immunotherapy. Bioorg Med. Chem. 102, 117677 (2024).","journal-title":"Bioorg Med. Chem."},{"key":"1359_CR128","doi-asserted-by":"publisher","first-page":"3333","DOI":"10.1158\/1078-0432.CCR-19-3548","volume":"26","author":"M Kraman","year":"2020","unstructured":"Kraman, M. et al. FS118, a bispecific antibody targeting LAG-3 and PD-L1, enhances T-cell activation resulting in potent antitumor activity. Clin. Cancer Res. 26, 3333\u20133344 (2020).","journal-title":"Clin. Cancer Res."},{"key":"1359_CR129","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1016\/j.cell.2017.10.033","volume":"171","author":"D Clift","year":"2017","unstructured":"Clift, D. et al. A method for the acute and rapid degradation of endogenous proteins. Cell 171, 1692\u20131706.e18 (2017).","journal-title":"Cell"},{"key":"1359_CR130","doi-asserted-by":"publisher","first-page":"16377","DOI":"10.1021\/jacs.1c08521","volume":"143","author":"H Zhang","year":"2021","unstructured":"Zhang, H. et al. Covalently engineered nanobody chimeras for targeted membrane protein degradation. J. Am. Chem. Soc. 143, 16377\u201316382 (2021).","journal-title":"J. Am. Chem. Soc."},{"key":"1359_CR131","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41586-020-2545-9","volume":"584","author":"SM Banik","year":"2020","unstructured":"Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291\u2013297 (2020).","journal-title":"Nature"},{"key":"1359_CR132","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/s41586-022-05235-6","volume":"610","author":"H Marei","year":"2022","unstructured":"Marei, H. et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature 610, 182\u2013189 (2022).","journal-title":"Nature"},{"key":"1359_CR133","doi-asserted-by":"publisher","first-page":"651","DOI":"10.3390\/jpm11070651","volume":"11","author":"A Botticelli","year":"2021","unstructured":"Botticelli, A. et al. The role of soluble LAG3 and soluble immune checkpoints profile in advanced head and neck cancer: a pilot study. J. Pers. Med. 11, 651 (2021).","journal-title":"J. Pers. Med."},{"key":"1359_CR134","doi-asserted-by":"publisher","first-page":"754961","DOI":"10.3389\/fimmu.2021.754961","volume":"12","author":"M Guo","year":"2021","unstructured":"Guo, M. et al. Serum LAG-3 predicts outcome and treatment response in hepatocellular carcinoma patients with transarterial chemoembolization. Front. Immunol. 12, 754961 (2021).","journal-title":"Front. Immunol."},{"key":"1359_CR135","doi-asserted-by":"publisher","first-page":"341","DOI":"10.3233\/CBM-181278","volume":"23","author":"N Li","year":"2018","unstructured":"Li, N., Jilisihan, B., Wang, W., Tang, Y. & Keyoumu, S. Soluble LAG3 acts as a potential prognostic marker of gastric cancer and its positive correlation with CD8+ T cell frequency and secretion of IL-12 and INF-\u03b3 in peripheral blood. Cancer Biomark. 23, 341\u2013351 (2018).","journal-title":"Cancer Biomark."},{"key":"1359_CR136","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.canlet.2005.04.015","volume":"235","author":"F Triebel","year":"2006","unstructured":"Triebel, F., Hacene, K. & Pichon, M. F. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 235, 147\u2013153 (2006).","journal-title":"Cancer Lett."},{"key":"1359_CR137","doi-asserted-by":"publisher","first-page":"7875","DOI":"10.1073\/pnas.1003345107","volume":"107","author":"J Matsuzaki","year":"2010","unstructured":"Matsuzaki, J. et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl Acad. Sci. USA 107, 7875\u20137880 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1359_CR138","doi-asserted-by":"publisher","first-page":"eabf5107","DOI":"10.1126\/scitranslmed.abf5107","volume":"13","author":"R Shen","year":"2021","unstructured":"Shen, R. et al. LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade. Sci. Transl. Med. 13, eabf5107 (2021).","journal-title":"Sci. Transl. Med."},{"key":"1359_CR139","doi-asserted-by":"publisher","first-page":"2724","DOI":"10.1200\/JCO.22.02072","volume":"41","author":"PA Ascierto","year":"2023","unstructured":"Ascierto, P. A. et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1\/programmed death ligand 1 therapy: results from the phase I\/IIa RELATIVITY-020 trial. J. Clin. Oncol. 41, 2724\u20132735 (2023).","journal-title":"J. Clin. Oncol."},{"key":"1359_CR140","doi-asserted-by":"publisher","first-page":"2261248","DOI":"10.1080\/2162402X.2023.2261248","volume":"12","author":"TN Gide","year":"2023","unstructured":"Gide, T. N. et al. Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3\u2009+\u2009anti-PD-1-based immunotherapies. Oncoimmunology 12, 2261248 (2023).","journal-title":"Oncoimmunology"},{"key":"1359_CR141","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.ymthe.2021.09.013","volume":"30","author":"Q Li","year":"2022","unstructured":"Li, Q. et al. PD-L1P146R is prognostic and a negative predictor of response to immunotherapy in gastric cancer. Mol. Ther. 30, 621\u2013631 (2022).","journal-title":"Mol. Ther."},{"key":"1359_CR142","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1158\/1078-0432.CCR-21-1229","volume":"28","author":"I Girault","year":"2022","unstructured":"Girault, I. et al. A PD-1\/PD-L1 proximity assay as a theranostic marker for PD-1 blockade in patients with metastatic melanoma. Clin. Cancer Res. 28, 518\u2013525 (2022).","journal-title":"Clin. Cancer Res."},{"key":"1359_CR143","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1158\/1078-0432.CCR-21-2649","volume":"28","author":"N Gavrielatou","year":"2022","unstructured":"Gavrielatou, N. et al. Association of PD-1\/PD-L1 co-location with immunotherapy outcomes in non-small cell lung cancer. Clin. Cancer Res. 28, 360\u2013367 (2022).","journal-title":"Clin. Cancer Res."},{"key":"1359_CR144","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1200\/JCO.22.01748","volume":"41","author":"L Sanchez-Magraner","year":"2023","unstructured":"Sanchez-Magraner, L. et al. Functional engagement of the PD-1\/PD-L1 complex but not PD-L1 expression is highly predictive of patient response to immunotherapy in non-small-cell lung cancer. J. Clin. Oncol. 41, 2561\u20132570 (2023).","journal-title":"J. Clin. Oncol."},{"key":"1359_CR145","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.ccell.2018.01.009","volume":"33","author":"CW Li","year":"2018","unstructured":"Li, C. W. et al. Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1. Cancer Cell 33, 187\u2013201.e10 (2018).","journal-title":"Cancer Cell"},{"key":"1359_CR146","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade4186","volume":"9","author":"C Huang","year":"2023","unstructured":"Huang, C. et al. PD-L1 methylation restricts PD-L1\/PD-1 interactions to control cancer immune surveillance. Sci. Adv. 9, eade4186 (2023).","journal-title":"Sci. Adv."},{"key":"1359_CR147","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53463-0","volume":"9","author":"K Bardhan","year":"2019","unstructured":"Bardhan, K. et al. Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells. Sci. Rep. 9, 17252 (2019).","journal-title":"Sci. Rep."},{"key":"1359_CR148","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1038\/s41591-026-04475-7","volume":"32","author":"M Lim","year":"2026","unstructured":"Lim, M. et al. Anti-LAG-3 with or without anti-PD-1 in recurrent glioblastoma: a phase 1 trial. Nat. Med. 32, 2449\u20132460 (2026).","journal-title":"Nat. Med."},{"key":"1359_CR149","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/imr.12520","volume":"276","author":"M Das","year":"2017","unstructured":"Das, M., Zhu, C. & Kuchroo, V. K. Tim-3 and its role in regulating anti-tumor immunity. Immunol. Rev. 276, 97\u2013111 (2017).","journal-title":"Immunol. Rev."},{"key":"1359_CR150","doi-asserted-by":"publisher","first-page":"4034","DOI":"10.1158\/1538-7445.AM2024-4034","volume":"84","author":"RR Maniyar","year":"2024","unstructured":"Maniyar, R. R. et al. Abstract 4034: Lag3 blockade enhances the anti-tumor effect of dual GITR agonism and PD-1 blockade in a preclinical melanoma model. Cancer Res. 84, 4034 (2024).","journal-title":"Cancer Res."},{"key":"1359_CR151","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1158\/1538-7445.AM2022-2080","volume":"82","author":"MJ Bernett","year":"2022","unstructured":"Bernett, M. J. et al. Abstract 2080: LAG3-targeted IL15\/IL15R\u03b1-Fc (LAG3\u2009\u00d7\u2009IL15) fusion proteins for preferential TIL expansion. Cancer Res. 82, 2080\u20132080 (2022).","journal-title":"Cancer Res."},{"key":"1359_CR152","doi-asserted-by":"publisher","first-page":"4062","DOI":"10.1158\/1538-7445.AM2024-4062","volume":"84","author":"J Killebrew","year":"2024","unstructured":"Killebrew, J. et al. Abstract 4062: a novel method for generating regulated cytokine therapeutics: safety and activity of a conditionally active cLAG3-IL2 capable of delivering IL2 to LAG3+ cells while remaining inert on LAG3\u2212 cells. Cancer Res. 84, 4062\u20134062 (2024).","journal-title":"Cancer Res."}],"container-title":["Nature Reviews Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41577-026-01359-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41577-026-01359-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41577-026-01359-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:02:47Z","timestamp":1791565367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41577-026-01359-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":152,"alternative-id":["1359"],"URL":"https:\/\/doi.org\/10.1038\/s41577-026-01359-2","relation":{},"ISSN":["1474-1733","1474-1741"],"issn-type":[{"value":"1474-1733","type":"print"},{"value":"1474-1741","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"assertion":[{"value":"10 September 2026","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2026","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.A.A.V. has patents covering lymphocyte activation gene 3 (LAG3), with others pending, and is entitled to a share of net income generated from the licensing of these patent rights for commercial development. D.A.A.V. is a co-founder and stockholder of Novasenta, Potenza, Tizona and Trishula; holds stock in Werewolf and Novasenta; receives royalties from patents licensed to BMS and Novasenta; serves on the scientific advisory boards of Werewolf, Apeximmune, T7\/Imreg Bio and Secarna; serves as a consultant for Third Arc Bio, Curie Bio, Ablytix, Radionetics Oncology and Ellipses; and receives funding from BMS and Novasenta. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}