SETDB1, also known as SET domain bifurcated histone lysine methyltransferase 1, ESET, or KMT1E, is an H3K9 methyltransferase. It plays a crucial role in gene silencing through catalyzing histone H3 lysine 9 (H3K9) methylation, especially di -/tri -methylation, promoting heterochromatin formation. It is involved in multiple biological processes such as immune cell function, retroelement silencing, and is associated with various diseases, particularly cancers [2,5,6]. Gene knockout (KO) or conditional knockout (CKO) mouse models are valuable tools to study its functions.

In mouse tumour models, in vivo CRISPR-Cas9 screens targeting chromatin regulators showed that SETDB1 and members of the HUSH and KAP1 complexes act as mediators of immune escape. SETDB1 amplification in human tumours is related to immune exclusion and resistance to immune checkpoint blockade. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and retroviral antigens, triggering TE-specific cytotoxic T cell responses [1]. In an ovarian cancer mouse model, SETDB1 knockout enhanced the antitumor effects of anti-PD-L1 immune checkpoint blockade, as inhibition of the SETDB1-TRIM28 complex upregulated PD-L1 and activated the cGAS-STING innate immune response pathway, increasing CD8+ T cell infiltration [3]. In a hepatosteatosis mouse model, hepatocyte-specific Setdb1-knockout (Setdb1-HKO) mice had significant lipid accumulation in the liver, indicating SETDB1's role in this disease [4].

In conclusion, SETDB1 is a key epigenetic regulator. Through model-based research, especially KO/CKO mouse models, its role in immune escape, tumour progression, and hepatosteatosis has been revealed. Understanding SETDB1's functions provides potential targets for immunotherapy and treatment of related diseases.