Pharmacologic inhibition of nonsense-mediated mRNA decay en-hances anti-tumour immunity
Whilst frameshift insertion/deletions can lead to the generation of highly immuno-genic neoantigens, frameshift-derived transcripts are often degraded by the non-sense-mediated mRNA decay (NMD) pathway. Leveraging multiomics and check-point inhibitor (CPI) response data from over 1,000 patients, we demonstrate that reduced expression, or genetic loss, of the NMD mediator SMG1 correlates with improved CPI response. SMG1 inhibition ex vivo and in vivo activates and expands tumour-reactive lymphocytes and potentiates CPI responses. Mechanistically, SMG1 inhibition stabilises frameshift-derived transcripts and increases the abun-dance and surface presentation of immunogenic neoantigens, shifting the ne-oepitope count from a low- to a high-tumour mutational burden (TMB)-like state. Co-culture of lymphocytes with tumour cells upon SMG1 inhibition induces antigen-dependent T cell activation and tumour cell killing. Our findings highlight SMG1 in-hibition as a promising immuno-oncology strategy to harness an untapped source of immunogenic neoantigens to enhance tumour immunogenicity and improve CPI efficacy, with broad applicability irrespective of TMB.