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<p>Gallbladder cancer (GBC), a lethal malignancy of the biliary tract, is associated with a poor clinical prognosis. Although chemo-immunotherapy combinations demonstrate preliminary efficacy, the molecular determinants of treatment response remain elusive. Emerging evidence implicates aberrant alternative splicing in modulating tumor immunity. Through an in vitro CRISPR/Cas9 screen, we identified SRSF2 as a key RNA-binding protein regulating PD-L1 expression. Intriguingly, SRSF2 does not directly bind PD-L1 mRNA. Multi-omics analyses (mRNA-seq, RIP-seq, and proteomics) revealed that SRSF2 induces exon skipping in hnRNPD, shifting isoform expression from full-length P45 to truncated P40. Functional studies established that P45—but not P40—binds to AU-rich elements in the PD-L1 3’-UTR to promote mRNA degradation. Leveraging this mechanism, we designed splice-switching antisense oligonucleotides (ASOs) that block SRSF2-mediated exon skipping, restoring P45 expression. This intervention effectively reduced PD-L1 levels and potentiated T-cell-mediated cytotoxicity in vitro and in vivo. These findings elucidate a splicing-centric mechanism of immune evasion and highlight the therapeutic potential of splicing modulation in cancer immunotherapy.</p><p></p>

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Splicing-mediated control of hnRNPD isoform switching by SRSF2 drives PD-L1-dependent immune evasion in gallbladder cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Zhao Cheng,
  • Lin Jiang,
  • Ming-yang Wang,
  • Qiu-yi Tang,
  • Jing-wei Zhao,
  • Zi-yi Yang,
  • Jun Gu,
  • Xiao-ling Song,
  • Ping Dong,
  • Li-jia Pan,
  • Yi-jun Shu,
  • Gong Wei

摘要

Gallbladder cancer (GBC), a lethal malignancy of the biliary tract, is associated with a poor clinical prognosis. Although chemo-immunotherapy combinations demonstrate preliminary efficacy, the molecular determinants of treatment response remain elusive. Emerging evidence implicates aberrant alternative splicing in modulating tumor immunity. Through an in vitro CRISPR/Cas9 screen, we identified SRSF2 as a key RNA-binding protein regulating PD-L1 expression. Intriguingly, SRSF2 does not directly bind PD-L1 mRNA. Multi-omics analyses (mRNA-seq, RIP-seq, and proteomics) revealed that SRSF2 induces exon skipping in hnRNPD, shifting isoform expression from full-length P45 to truncated P40. Functional studies established that P45—but not P40—binds to AU-rich elements in the PD-L1 3’-UTR to promote mRNA degradation. Leveraging this mechanism, we designed splice-switching antisense oligonucleotides (ASOs) that block SRSF2-mediated exon skipping, restoring P45 expression. This intervention effectively reduced PD-L1 levels and potentiated T-cell-mediated cytotoxicity in vitro and in vivo. These findings elucidate a splicing-centric mechanism of immune evasion and highlight the therapeutic potential of splicing modulation in cancer immunotherapy.