Mutant TP53 hijacks RNA-splicing factor RBM28 to suppress double-strand RNA triggered antitumor immunity

Here, we demonstrate that DNA-binding domain mutations of TP53 unexpectedly confer a transcriptional regulatory function, directly driving RNA-splicing factor RBM28 overexpression. Overexpressed RBM28 excessively splices transposon elements, inhibiting dsRNA formation, thereby suppressing dsRNA-triggered type I IFN signaling and subsequent anti-tumor immunity.

We demonstrate in mouse tumorigenesis models and human multi-stage esophageal cancer development that mutp53-driven aberrant RBM28/dsRNA/IFN axis plays a crucial role in cancer initiation, progression and resistance to immune checkpoint blockade (ICB) therapy through innate immune suppression. Pan-cancer analysis indicates that this mechanism underlies ICB resistance in most cancers. Pharmacological restoration of normal p53 conformation or targeted RNA-splicing inhibition enhances anti-tumor immunity and ICB efficacy.