RNA Surveillance Failure as a Determinant of Hypoxic Immune Escape and Metastatic Tumour State.

Metastasis remains the dominant cause of cancer mortality, yet genetic alteration alone fails to explain the spatial plasticity, immune escape, and therapy resistance characteristic of advanced solid tumours. Here we advance an RNA-centric framework in which exon-mediated activation of transcription starts (EMATS) amplifies transcriptional output, while hierarchical RNA surveillance-nuclear decay and cytoplasmic nonsense-mediated decay (NMD)-determines transcript fate downstream of transcription. In hypoxic tumour cores, EMATS-driven RNA overproduction overwhelms surveillance capacity, causing RNA fate collapse, proteostasis stress, destabilisation of proteasome-HLA coupling, and immune invisibility. In contrast, invasive tumour margins preserve RNA surveillance, maintaining antigen presentation and metastatic signalling. This framework explains immune escape independently of mutation burden or cytokine excess. It reconciles paradoxes in immunotherapy response, and positions RNA fate as a tractable axis for biomarker development and therapeutic stratification.