[摘 要] 可变剪接是转录后水平的基因表达调控机制，也是导致真核生物转录组和蛋白质组多样性的重要途径。然而，可变 剪接的异常是驱动肿瘤进展的重要推手。在肿瘤微环境中，肿瘤细胞、免疫细胞及肿瘤中其他类型细胞中mRNA的异常剪接，不 仅参与塑造肿瘤细胞的恶性生物学行为和免疫逃逸，还促进支持肿瘤进展的免疫抑制性微环境的形成。靶向肿瘤相关剪接体组 分、剪接调控因子、可变剪接产生的蛋白异构体和mRNA变异体，以及异常可变剪接产生的肿瘤新抗原已成为肿瘤治疗的新策 略，已有基于可变剪接的肿瘤生物治疗项目进入到Ⅰ期临床研究阶段。基于可变剪接的肿瘤治疗面临安全性、长读测序和算法 优化、核酸类药物递送等许多尚待解决的科学和技术问题，这些挑战的解决将为精准筛选肿瘤相关靶点和高免疫原性新抗原，突 破传统疗法耐药瓶颈，增强免疫检查点阻断和CAR-T细胞等疗效提供新策略，开辟新领域。

[Abstract] Alternative splicing, a post-transcriptional regulatory mechanism of gene expression, contributes to the diversity of the transcriptome and proteome in eukaryotes. However, aberrant alternative splicing serves as a significant driver of tumor progression, where abnormal splicing in tumor cells, immune cells, and other cell types within the tumor microenvironment collectively results in malignant behaviors of cancer cells, immune evasion, and the immunosuppressive milieu that supports tumor advancement. Targeting tumor-associated spliceosomes, splicing regulatory factors, splicing isoforms and variants, as well as tumor neoantigens generated by aberrant alternative splicing, has emerged as a novel strategy in cancer biotherapy. Some alternative splicing-based antitumor biotherapy programs have progressed to phase Ⅰ clinical trials. Alternative splicing-based tumor therapy still faces scientific and technological challenges such as safety, optimization of long-read sequencing and bioinformatics algorithm, and nucleic acid drug delivery. Addressing these challenges will provide new tumor therapy strategies and open up new frontiers for precisely screening tumor-related targets and highly immunogenic neoantigens, overcoming drug resistance in traditional therapies, and enhancing the efficacy of immune checkpoint blockade, CAR-T cell therapy, and other treatments.

国家自然科学基金（No. 91942304）