Small cell lung cancer exhibits hyperactive nonsense-mediated decay (NMD) that correlates with tumor mutational burden, and NMD inhibition creates a dual therapeutic vulnerability by triggering TMB-dependent ER stress-mediated apoptosis in cancer cells while simultaneously upregulating neoantigen presentation to enhance T cell-mediated immune responses, thereby enabling effective tumor control in vivo and improving immunotherapy efficacy.

Small cell lung cancer (SCLC) is among the deadliest cancers with excessive somatic alterations, expectedly resulting in immunogenic epitopes. However, patient benefit from immunotherapy is limited. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC depends on NMD for cellular homeostasis and immune evasion. NMD inhibition impaired SCLC proliferation and induced ER stress-dependent apoptosis in a TMB-dependent manner, thereby enabling pharmacological inhibition in vivo which effectively controlled tumor growth. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC – as a TMBhigh cancer – relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.