Dual inhibition of the nonsense mediated mRNA decay enhances tumour immunogenicity, drives immunoediting, and potentiates checkpoint blockade

Abstract

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepancy is the activity of nonsense-mediated mRNA decay (NMD), a cellular quality-control pathway that degrades mutant transcripts, potentially reducing the presentation of neoantigens that would otherwise stimulate anti-tumour immunity. To address this, we identified publicly available small-molecule inhibitors targeting the NMD factors SMG5 and SMG7 (NMDi), which we have prioritise as the NMD components most strongly associated with NMD efficiency across TCGA tumours, and evaluated their therapeutic potential in vivo. In a syngeneic, DNA repair deficient mouse model of lung adenocarcinoma, NMDi treatment alone substantially reduced tumour burden, and its combination with anti-PD-1 therapy led to additive benefit either treatment alone. These effects were immune-dependent and specifically required CD8{square} T cells. Transcriptomic and single-cell analyses revealed that NMDi reprograms the tumour immune microenvironment, enriching for clonally expanded, cytotoxic CD8{square} T cells and altering macrophage states toward those associated with tumour regression. Whole-genome sequencing of tumours revealed that NMDi also promotes immunoediting, leading to negative selection against immunogenic mutations and coding indels, with selective pressure comparable to or greater than that induced by anti-PD-1 treatment. Guided by these results, we generated a new protein language model trained on tumour mutations that can identify neopeptides with immunogenic properties, revealing that the NMDi tumour landscape provides a rich genomic and immunopeptidomic setting for exposing neoantigens that evade immunoediting. Together, these pre-clinical and integrative genomic-transcriptomic insights position NMD inhibition as a promising immunostimulatory strategy that can potentiate immune checkpoint blockade efficacy in tumours.