The tumor immune microenvironment is influenced by the epigenetic landscape of the tumor. Here, we have identified the SETDB1–TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR–Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a suppressor of PD-L1 expression. We then revealed that expression of the SETDB1–TRIM28 complex negatively correlated with infiltration of effector CD8+ T cells. Inhibition of SETDB1–TRIM28 simultaneously upregulated PD-L1 and activated the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) innate immune response pathway to increase infiltration of CD8+ T cells. Mechanistically, SETDB1–TRIM28 inhibition led to micronuclei formation in the cytoplasm, which is known to activate the cGAS–STING pathway. Thus, SETDB1–TRIM28 inhibition bridges innate and adaptive immunity. Indeed, SETDB1 knockout enhanced the antitumor effects of immune checkpoint blockade with anti–PD-L1 in a mouse model of ovarian cancer in a cGAS-dependent manner. Our findings establish the SETDB1–TRIM28 complex as a regulator of antitumor immunity and demonstrate that its loss activates cGAS–STING innate immunity to boost the antitumor effects of immune checkpoint blockade.

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