Increased level of spontaneous DNA damage in SMAD4‐deficient PDAC cells stimulated STING‐mediated IFN‐I signaling to promote tumor cell major histocompatibility complex‐I (MHC‐I) expression and cDC1‐mediated antigen cross‐presentation, which together boosted antitumor immunity. Here, SMAD4 is linked to neoplasm.