In particular, we report that IFN-α in combination with epigenetic drugs inhibits the proliferation and the metastatic behavior of KRAS-mutated highly metastatic SW620 cells and patient-derived self-renewing CTSC#18 CSCs, by two main mechanisms: (i) shutting down metastatic cellular pathways, including CXCR4, ERK1/2 and AKT signals; (ii) inducing apoptosis with ICD features able to deliver signals to DCs that, in turn, increase their capability to phagocytose drug-treated cancer cells. Here, MAPK3 is linked to cancer.