剪接因子受到几种类型的血液系统和实体恶性肿瘤中反复出现的体细胞突变和拷贝数变异的影响，这通常被视为剪接畸变可以驱动癌症发生和进展的初步证据。然而，许多剪接体成分也在 DNA 修复和其他细胞过程中“兼职”，这使得它们在癌症中的确切作用难以确定。尽管如此，很少有人否认 mRNA 剪接失调是大多数癌症的普遍特征。正确解释这些分子指纹可以揭示新的肿瘤脆弱性和尚未开发的治疗机会。然而，多重技术挑战、挥之不去的误解和悬而未决的问题阻碍了临床转化。首先，由于短读长 RNA 测序不擅长解析完整 mRNA 异构体的局限性，以及长读长 RNA 测序固有的浅读长深度，癌症中剪接畸变的总体情况尚未明确定义。尤其是在单细胞水平上。尽管已知个体癌症相关亚型会促进癌症进展，但广泛的剪接改变可能是人类癌症的一个同样重要且可能更容易采取行动的特征。这就是说，除了“修复”错误剪接的转录本之外，可能的治疗途径还包括使用小分子剪接体抑制剂加剧剪接畸变、使用合成致死方法针对反复出现的剪接畸变以及训练免疫系统识别剪接衍生的新抗原.© 2024。施普林格自然有限公司。

Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens.© 2024. Springer Nature Limited.