The study investigates the oncogenic functions of mutant p53 (mutp53) proteins, which can promote tumor development and progression despite their loss-of-function (LOF) effects. The researchers found that mutp53 interacts with minichromosome maintenance complex components (MCMs), leading to replication stress and chromosomal instability (CIN). This CIN triggers a tumor cell-intrinsic cytosolic DNA response, activating the cGAS-STING pathway and downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. This signaling pathway promotes tumor metastasis and an immunosuppressive tumor microenvironment by antagonizing interferon (IFN) signaling and regulating genes associated with pro-tumorigenic inflammation. The findings highlight the importance of CIN in mutp53-induced oncogenic phenotypes and suggest that targeting the NC-NF-κB signaling pathway could be a potential therapeutic strategy for cancers with TP53 inactivation-induced CIN.The study investigates the oncogenic functions of mutant p53 (mutp53) proteins, which can promote tumor development and progression despite their loss-of-function (LOF) effects. The researchers found that mutp53 interacts with minichromosome maintenance complex components (MCMs), leading to replication stress and chromosomal instability (CIN). This CIN triggers a tumor cell-intrinsic cytosolic DNA response, activating the cGAS-STING pathway and downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. This signaling pathway promotes tumor metastasis and an immunosuppressive tumor microenvironment by antagonizing interferon (IFN) signaling and regulating genes associated with pro-tumorigenic inflammation. The findings highlight the importance of CIN in mutp53-induced oncogenic phenotypes and suggest that targeting the NC-NF-κB signaling pathway could be a potential therapeutic strategy for cancers with TP53 inactivation-induced CIN.