In vivo CRISPR screens identify CBX4 as an epigenetic regulator for cancer immunotherapy - PubMed
9 hours ago
- #Epigenetics
- #Cancer Immunotherapy
- #CRISPR Screen
- In vivo CRISPR screens in mouse tumor models treated with immune checkpoint blockade (ICB) identified Chromobox 4 (CBX4) as a negative regulator of the immune tumor microenvironment.
- CBX4 expression is high in tumor cells and immunosuppressive macrophages in non-responders to anti-PD-1 therapy, and its deficiency enhances anti-tumor immunity and ICB sensitivity by increasing CD8+ T cell and NK cell activity.
- Mechanistically, CBX4 silences endogenous retroelements (e.g., RLTR4-Mm-int) via H3K9me3 and H3K27me3; its loss activates RNA-sensing pathways and type I interferon response, creating an inflamed tumor microenvironment.
- CBX4 negatively correlates with immune responses, retrotransposon levels, and prognosis in hepatocellular carcinoma patients undergoing ICB therapy, positioning it as an epigenetic immune checkpoint and potential therapeutic target.