Splicing-driven post-translational dysregulation: a new frontier for precision cancer medicine and immunotherapy

Cancer is a disease marked by widespread molecular dysregulation, including alterations in gene expression, signaling pathways, and protein function. Among the critical regulators of protein function are post-translational modifications (PTMs), which fine-tune protein stability, activity, localization, and interactions. At the same time, more and more data has shown that mutations in parts of the splicing machinery, such as SF3B1, SRSF2, U2AF1, and ZRSR2, are common causes of different types of hematologic and solid tumors. Although the transcriptome implications of these mutations have been thoroughly delineated, their subsequent impacts on PTM regulation are still predominantly unexamined. This review seeks to address this deficiency by emphasizing the nascent connections between spliceosome mutations and the alteration of PTM landscapes in cancer. We suggest that modified splicing of PTM-related enzymes and substrates could significantly transform the cancer proteome, providing novel mechanistic insights and therapeutic prospects. We also look into how splicing-driven PTM changes, especially those that affect ubiquitination pathways and other important modification systems, affect the immune landscape of tumors. This gives us new information about how tumors with splicing mutations become more fit by changing the pathways that control the immune system and tumor surveillance.