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

TP53 mutation may not only compromise its multifaceted tumor-suppressive functions but also 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 double-stranded RNA (dsRNA) formation, thereby suppressing dsRNA-triggered type I interferon (IFN) signaling and subsequent anti-tumor immunity. We demonstrate in mouse tumorigenesis models and human multi-stage esophageal cancer development that mutant p53 (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 an important function of mutp53 in establishing immunosuppressive tumor microenvironment, which provides an actionable framework for intervention and therapy in TP53-mutated cancers. Mutant p53 (mutp53) drives tumor immune evasion partly through restricting innate immune sensing triggered by transposable elements (TEs). Here, the authors find that mutations in the DNA-binding domain enable mutp53 to transcriptionally activate the RNA-splicing factor RBM28, leading to excessive splicing of TE transcripts and suppression of antitumor immunity in esophageal cancer.