In this study, we sought to investigate whether a combination of a vascular disruption agent (combretastatin A4 phosphate—CA4P) and a cGAS-STING pathway activator (cGAMP) could lead to an increased therapeutic potential in targeting two poorly immunogenic, difficult-to-treat MHC I-deficient (B16-F10 melanoma) and MHC I-positive (4T1 breast cancer) tumor models and, if it is so, which immune cells are mainly involved in cancer cell eradication. Here, CGAS is linked to neoplasm.