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

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 survival. Expression analysis in patient tumors reveals correlations between SMG1 and drug-targeted splicing regulators, supporting a functional link between splicing and NMD. Together, our findings identify splicing modulators as inadvertent NMD inhibitors that simultaneously boost tumor antigenicity and can be used to selectively target NMD-addicted tumors.