PP039 Inhibition of CAF-1 histone chaperone complex triggers cytosolic DNA and dsRNA sensing pathways and induces intrinsic immunity of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide but only a few FDA-approved drugs are available for advanced HCC patients. Immune checkpoint inhibitor (ICI) has emerged as new and effective treatment HCC, yet quarter patients responsive to ICI treatment. Epigenetic deregulation plays critical role in initiation progression whereas contribution histone chaperones variants liver carcinogenesis remains largely unexplored. Histone Chaperone complex Chromatin assembly factor 1 (CAF-1) knockout cell lines were established using CRISPR/Cas9 system. The effects CAF-1 studied lines, nude mice, immunocompetent mice. RNA-Seq was applied measure expression genes repetitive elements. ChIP-Seq ATAC-Seq used explore changes epigenome. significantly upregulated human mouse HCCs associated with poor prognosis Knockout remarkably suppressed growth both vitro vivo models. Mechanistically, depletion induced replicative stress chromatin instability, which eventually led cytoplasmic DNA leakage micronuclei. Also, analyses revealed massive H3.3 variant replacement upon knockout. Enrichment euchromatic increased accessibility activated endogenous retrovirus elements (ERVs), phenomenon known viral mimicry. Altogether, cytosolic micronuclei ERVs recognized ectopic by STING dsRNA sensing pathways, respectively. As result, inflammatory response anti-tumor immune surveillance thereby enhanced anti-cancer effect therapy HCC. Our findings suggest that essential development, targeting may awaken work cooperatively therapy.