Following epigenetic STING (stimulator of interferon genes) derepression, inhibition of the MPS1 kinase strongly reactivated cGAS-STING signaling in mutations in both the oncogene KRAS and the tumor suppressor kinase LKB/STK11. Exploiting these findings could lead to a new therapeutic strategy to target treatment-refractory tumors with mutations in KL tumors, which have mutations in both KRAS and LKB1/STK11.