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

TP53 mutation may not only compromise its multifaceted tumor-suppressive functions but confer oncogenic properties. 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. Collectively, our study has unveiled a novel function of mutp53 in establishing immunosuppressive tumor microenvironment, which provides an actionable framework for new avenue for intervention and therapy in TP53-mutated cancers.