Imbalanced p53-RB signaling triggers cGAS-STING-mediated immune activation in early oral cancer development.

Combined alterations of TP53 and CDKN2A are frequently observed in head and neck squamous cell carcinoma (HNSCC); however, their cooperative roles in oral carcinogenesis remain unclear. To investigate their interaction under carcinogenic stress, we generated Cdkn2a knock-in (KI) mice harboring a human-relevant R80X truncating mutation, along with Trp53 loss-of-function (LOF) mutants and exposed them to 4-nitroquinoline-1-oxide (4NQO). Partial loss of Cdkn2a combined with Trp53 heterozygosity was associated with increased STING-related inflammatory signaling and enhanced T-cell/NK-cell-associated immune infiltration, coinciding with delayed malignant progression. Enhanced production of proinflammatory cytokines and chemokines further indicated selective activation of the cGAS-STING-NF-κB axis. Analysis of the TCGA-HNSC cohort showed that combined TP53/CDKN2A alterations significantly separated overall survival and were associated with distinct survival patterns. These findings reveal a previously unrecognized mechanism by which imbalanced p53-RB signaling triggers tumor immunity during the early stages of oral carcinogenesis.