Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Inactivating TP53 mutations lead to loss of p53 function but can also result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53), promoting tumor development and progression. While the GOF activities of TP53 mutations are well documented, the mechanisms remain poorly understood. This study investigates the mutp53 interactome and finds that mutp53 targets minichromosome maintenance complex components (MCMs), leading to replication stress and chromosomal instability (CIN). This results in a tumor cell-autonomous cytosolic DNA response involving cGAS-STING-dependent activation of downstream non-canonical NF-κB signaling, which promotes tumor metastasis and an immunosuppressive tumor microenvironment by antagonizing interferon signaling and regulating pro-tumorigenic inflammation. The findings highlight the role of p53 as a genome guardian and its inactivation during tumor development and progression. The study shows that mutp53 interacts with MCMs, leading to replication stress and CIN, which activate cytosolic DNA and cGAS-STING pathways, resulting in NC-NF-κB signaling. This signaling promotes tumor cell invasion, metastasis, and immunosuppression. The study also demonstrates that mutp53-MCM5-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling antagonizes interferon signaling and regulates inflammation-related genes, contributing to tumor progression and resistance to anti-tumor immunity. The findings suggest that targeting tumor cell-intrinsic NC-NF-κB signaling could be an effective strategy for treating cancers with TP53 inactivation-induced CIN.Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Inactivating TP53 mutations lead to loss of p53 function but can also result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53), promoting tumor development and progression. While the GOF activities of TP53 mutations are well documented, the mechanisms remain poorly understood. This study investigates the mutp53 interactome and finds that mutp53 targets minichromosome maintenance complex components (MCMs), leading to replication stress and chromosomal instability (CIN). This results in a tumor cell-autonomous cytosolic DNA response involving cGAS-STING-dependent activation of downstream non-canonical NF-κB signaling, which promotes tumor metastasis and an immunosuppressive tumor microenvironment by antagonizing interferon signaling and regulating pro-tumorigenic inflammation. The findings highlight the role of p53 as a genome guardian and its inactivation during tumor development and progression. The study shows that mutp53 interacts with MCMs, leading to replication stress and CIN, which activate cytosolic DNA and cGAS-STING pathways, resulting in NC-NF-κB signaling. This signaling promotes tumor cell invasion, metastasis, and immunosuppression. The study also demonstrates that mutp53-MCM5-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling antagonizes interferon signaling and regulates inflammation-related genes, contributing to tumor progression and resistance to anti-tumor immunity. The findings suggest that targeting tumor cell-intrinsic NC-NF-κB signaling could be an effective strategy for treating cancers with TP53 inactivation-induced CIN.