{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:23:44Z","timestamp":1791912224977,"version":"4.3.4"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103230"],"award-info":[{"award-number":["82103230"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"DOI":"10.1038\/s41467-024-53561-2","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:02:53Z","timestamp":1729641773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A splicing isoform of PD-1 promotes tumor progression as a potential immune checkpoint"],"prefix":"10.1038","volume":"15","author":[{"given":"Xuetong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongfeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinmin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyou","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songzhe","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiang","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9744-4251","authenticated-orcid":false,"given":"Rong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0262-4549","authenticated-orcid":false,"given":"Shan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"53561_CR1","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252\u2013264 (2012).","journal-title":"Nat. Rev. Cancer"},{"key":"53561_CR2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/j.1600-065X.2009.00769.x","volume":"229","author":"RI Nurieva","year":"2009","unstructured":"Nurieva, R. I., Liu, X. & Dong, C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol. Rev. 229, 88\u2013100 (2009).","journal-title":"Immunol. Rev."},{"key":"53561_CR3","doi-asserted-by":"publisher","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","volume":"11","author":"Y Ishida","year":"1992","unstructured":"Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887\u20133895 (1992).","journal-title":"EMBO J."},{"key":"53561_CR4","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","volume":"26","author":"ME Keir","year":"2008","unstructured":"Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677\u2013704 (2008).","journal-title":"Annu. Rev. Immunol."},{"key":"53561_CR5","doi-asserted-by":"publisher","first-page":"6640","DOI":"10.1073\/pnas.1921445117","volume":"117","author":"X Wang","year":"2020","unstructured":"Wang, X. et al. Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy. Proc. Natl Acad. Sci. USA 117, 6640\u20136650 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"53561_CR6","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","volume":"192","author":"GJ Freeman","year":"2000","unstructured":"Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027\u20131034 (2000).","journal-title":"J. Exp. Med."},{"key":"53561_CR7","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/85330","volume":"2","author":"Y Latchman","year":"2001","unstructured":"Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261\u2013268 (2001).","journal-title":"Nat. Immunol."},{"key":"53561_CR8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/bjc.2017.434","volume":"118","author":"RW Jenkins","year":"2018","unstructured":"Jenkins, R. W., Barbie, D. A. & Flaherty, K. T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 118, 9\u201316 (2018).","journal-title":"Br. J. Cancer"},{"key":"53561_CR9","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","volume":"168","author":"P Sharma","year":"2017","unstructured":"Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707\u2013723 (2017).","journal-title":"Cell"},{"key":"53561_CR10","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2006.06.023","volume":"126","author":"BJ Blencowe","year":"2006","unstructured":"Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37\u201347 (2006).","journal-title":"Cell"},{"key":"53561_CR11","doi-asserted-by":"publisher","first-page":"152","DOI":"10.3892\/br.2014.407","volume":"3","author":"Y Wang","year":"2015","unstructured":"Wang, Y. et al. Mechanism of alternative splicing and its regulation. Biomed. Rep. 3, 152\u2013158 (2015).","journal-title":"Biomed. Rep."},{"key":"53561_CR12","doi-asserted-by":"publisher","first-page":"7647","DOI":"10.1158\/0008-5472.CAN-04-1910","volume":"64","author":"JP Venables","year":"2004","unstructured":"Venables, J. P. Aberrant and alternative splicing in cancer. Cancer Res. 64, 7647\u20137654 (2004).","journal-title":"Cancer Res."},{"key":"53561_CR13","doi-asserted-by":"publisher","first-page":"5311","DOI":"10.1038\/onc.2013.533","volume":"33","author":"S Oltean","year":"2014","unstructured":"Oltean, S. & Bates, D. O. Hallmarks of alternative splicing in cancer. Oncogene 33, 5311\u20135318 (2014).","journal-title":"Oncogene"},{"key":"53561_CR14","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1002\/eji.201242529","volume":"43","author":"FJ Ward","year":"2013","unstructured":"Ward, F. J. et al. The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur. J. Immunol. 43, 1274\u20131285 (2013).","journal-title":"Eur. J. Immunol."},{"key":"53561_CR15","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nri1497","volume":"4","author":"KW Lynch","year":"2004","unstructured":"Lynch, K. W. Consequences of regulated pre-mRNA splicing in the immune system. Nat. Rev. Immunol. 4, 931\u2013940 (2004).","journal-title":"Nat. Rev. Immunol."},{"key":"53561_CR16","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.cellimm.2005.07.007","volume":"235","author":"C Nielsen","year":"2005","unstructured":"Nielsen, C., Ohm-Laursen, L., Barington, T., Husby, S. & Lillevang, S. T. Alternative splice variants of the human PD-1 gene. Cell Immunol. 235, 109\u2013116 (2005).","journal-title":"Cell Immunol."},{"key":"53561_CR17","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1038\/mt.2013.63","volume":"21","author":"J Zhou","year":"2013","unstructured":"Zhou, J. et al. Potentiating functional antigen-specific CD8+ T cell immunity by a novel PD1 isoform-based fusion DNA vaccine. Mol. Ther. 21, 1445\u20131455 (2013).","journal-title":"Mol. Ther."},{"key":"53561_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.678400","volume":"12","author":"C Ponce de Le\u00f3n","year":"2021","unstructured":"Ponce de Le\u00f3n, C. et al. Significance of PD1 alternative splicing in celiac disease as a novel source for diagnostic and therapeutic target. Front. Immunol. 12, 678400 (2021).","journal-title":"Front. Immunol."},{"key":"53561_CR19","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1093\/intimm\/8.5.765","volume":"8","author":"Y Agata","year":"1996","unstructured":"Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765\u2013772 (1996).","journal-title":"Int. Immunol."},{"key":"53561_CR20","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.immuni.2016.04.020","volume":"44","author":"JH Esensten","year":"2016","unstructured":"Esensten, J. H., Helou, Y. A., Chopra, G., Weiss, A. & Bluestone, J. A. CD28 costimulation: from mechanism to therapy. Immunity 44, 973\u2013988 (2016).","journal-title":"Immunity"},{"key":"53561_CR21","doi-asserted-by":"publisher","first-page":"12293","DOI":"10.1073\/pnas.192461099","volume":"99","author":"Y Iwai","year":"2002","unstructured":"Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293\u201312297 (2002).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"53561_CR22","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.molcel.2019.04.005","volume":"74","author":"X Tu","year":"2019","unstructured":"Tu, X. et al. PD-L1 (B7-H1) competes with the RNA exosome to regulate the DNA damage response and can be targeted to sensitize to radiation or chemotherapy. Mol. Cell 74, 1215\u20131226.e1214 (2019).","journal-title":"Mol. Cell"},{"key":"53561_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105741","volume":"170","author":"H Ying","year":"2021","unstructured":"Ying, H. et al. Non-cytomembrane PD-L1: An atypical target for cancer. Pharmacol. Res. 170, 105741 (2021).","journal-title":"Pharmacol. Res."},{"key":"53561_CR24","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1084\/jem.20090847","volume":"206","author":"LM Francisco","year":"2009","unstructured":"Francisco, L. M. et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015\u20133029 (2009).","journal-title":"J. Exp. Med."},{"key":"53561_CR25","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1073\/pnas.0712278105","volume":"105","author":"DY Lin","year":"2008","unstructured":"Lin, D. Y. et al. The PD-1\/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl Acad. Sci. USA 105, 3011\u20133016 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"53561_CR26","doi-asserted-by":"publisher","first-page":"2341","DOI":"10.1016\/j.str.2015.09.010","volume":"23","author":"KM Zak","year":"2015","unstructured":"Zak, K. M. et al. Structure of the complex of human programmed death 1, PD-1, and its ligand PD-L1. Structure 23, 2341\u20132348 (2015).","journal-title":"Structure"},{"key":"53561_CR27","doi-asserted-by":"publisher","first-page":"101960","DOI":"10.1016\/j.isci.2020.101960","volume":"24","author":"K Magiera-Mularz","year":"2021","unstructured":"Magiera-Mularz, K. et al. Human and mouse PD-L1: similar molecular structure, but different druggability profiles. iScience 24, 101960 (2021).","journal-title":"iScience"},{"key":"53561_CR28","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.canlet.2020.10.046","volume":"498","author":"N Li","year":"2021","unstructured":"Li, N. et al. Tumor perfusion enhancement by ultrasound stimulated microbubbles potentiates PD-L1 blockade of MC38 colon cancer in mice. Cancer Lett. 498, 121\u2013129 (2021).","journal-title":"Cancer Lett."},{"key":"53561_CR29","doi-asserted-by":"publisher","first-page":"155","DOI":"10.4049\/jimmunol.1102042","volume":"188","author":"SM Liu","year":"2012","unstructured":"Liu, S. M. et al. Overexpression of the Ctla-4 isoform lacking exons 2 and 3 causes autoimmunity. J. Immunol. 188, 155\u2013162 (2012).","journal-title":"J. Immunol."},{"key":"53561_CR30","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1084\/jem.20180870","volume":"216","author":"B Gong","year":"2019","unstructured":"Gong, B. et al. Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer. J. Exp. Med. 216, 982\u20131000 (2019).","journal-title":"J. Exp. Med."},{"key":"53561_CR31","doi-asserted-by":"publisher","first-page":"6314","DOI":"10.3390\/ijms24076314","volume":"24","author":"X Zheng","year":"2023","unstructured":"Zheng, X., Chen, X. & Wu, W. The regulatory axis of PD-L1 isoform 2\/TNF\/T cell proliferation is required for the canonical immune-suppressive effects of PD-L1 isoform 1 in liver cancer. Int. J. Mol. Sci. 24, 6314 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"53561_CR32","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1080\/15476286.2019.1659080","volume":"16","author":"J Sun","year":"2019","unstructured":"Sun, J., Bai, J., Jiang, T., Gao, Y. & Hua, Y. Modulation of PDCD1 exon 3 splicing. RNA Biol. 16, 1794\u20131805 (2019).","journal-title":"RNA Biol."},{"key":"53561_CR33","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1136\/gutjnl-2022-327133","volume":"72","author":"Z Tan","year":"2023","unstructured":"Tan, Z. et al. Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut 72, 1568\u20131580 (2023).","journal-title":"Gut"},{"key":"53561_CR34","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","volume":"25","author":"KJ Livak","year":"2001","unstructured":"Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25, 402\u2013408 (2001).","journal-title":"Methods"},{"key":"53561_CR35","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.ccell.2016.03.004","volume":"29","author":"L Qu","year":"2016","unstructured":"Qu, L. et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer cell 29, 653\u2013668 (2016).","journal-title":"Cancer cell"},{"key":"53561_CR36","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1158\/0008-5472.CAN-20-1619","volume":"81","author":"Y Gu","year":"2021","unstructured":"Gu, Y. et al. DMDRMR-mediated regulation of m(6)A-modified CDK4 by m(6)A reader IGF2BP3 drives ccRCC progression. Cancer Res. 81, 923\u2013934 (2021).","journal-title":"Cancer Res."},{"key":"53561_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).","journal-title":"Genome Biol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53561-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53561-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53561-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:03:01Z","timestamp":1729641781000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-53561-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,23]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["53561"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-53561-2","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,23]]},"assertion":[{"value":"22 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9114"}}