Pharmacological perturbation of splicing elicits SMG1 reduction: Implications for cancer therapy.

ABSTRACT: Nonsense-mediated mRNA decay (NMD) is an RNA quality control pathway that degrades transcripts containing premature termination codons (PTCs). While the role of NMD in modulating tumor antigenicity and immune evasion is increasingly appreciated, its interaction with splicing remains poorly understood. We uncover a mechanism by which the splicing modulators enhance tumor immunogenicity not only by inducing aberrant splicing events that generate neoantigens but also by suppressing NMD activity through the downregulation of SMG1. This stabilizes PTC-containing transcripts, potentially expanding the pool of neoantigens. Furthermore, we demonstrate that splicing modulation exerts enhanced cytotoxic effects in microsatellite instability (MSI) tumors, which are particularly reliant on NMD for sur

SUBMITTER: Barainka M 

PROVIDER: S-EPMC12857400 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature