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Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA\u2010seq analysis, it is found high expression of the splicing factor polypyrimidine region\u2010 binding protein 3 (PTBP3) in GBC. Multi\u2010omics analysis revealed that PTBP3 promoted exon skipping of interleukin\u201018 (IL\u201018), resulting in the expression of \u0394IL\u201018, an isoform specifically expressed in tumors. That \u0394IL\u201018 promotes GBC immune escape by down\u2010regulating FBXO38 transcription levels in CD8+T cells to reduce PD\u20101 ubiquitin\u2010mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and \u0394IL\u201018 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked \u0394IL\u201018 production displayed anti\u2010tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL\u201018 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL\u201018 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL\u201018 pre\u2010mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.202406633","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:50:20Z","timestamp":1723132220000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["PTBP3 Mediates IL\u201018 Exon Skipping to Promote Immune Escape in Gallbladder Cancer"],"prefix":"10.1002","volume":"11","author":[{"given":"Cheng","family":"Zhao","sequence":"first","affiliation":[{"name":"Laboratory of General Surgery and Department of General Surgery Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine  No. 1665 Kongjiang Road Shanghai 200092 China"},{"name":"Shanghai Key Laboratory of Biliary Tract Disease Research  No. 1665 Kongjiang Road Shanghai 200092 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