Elevated CHAF1A Suppresses Type I Interferon Production and Causes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma

Abstract In esophageal squamous cell carcinoma (ESCC), chemoradiotherapy potentiates the effects of immune checkpoint inhibitors by activating the tumor-intrinsic innate immune response. However, ESCC cells frequently suppress this activation, which contributes to the high rates of immunotherapy resistance (70%–80%) observed clinically. Thus, identifying intracellular suppressors of this innate immune response remains an unmet critical need. Herein, through multiomics analyses, we identify the chromatin assembly factor CHAF1A as a suppressor of the tumor-intrinsic innate immune response in ESCC. We found that CHAF1A was overexpressed in ESCC and negatively correlated with type I interferon production and CD8+ T-cell infiltration. Mechanistically, CHAF1A maintained heterochromatin silencing mediated by H3K9me3, thereby repressing endogenous retroviruses. This suppression prevented the accumulation of double-stranded RNA and the subsequent activation of the MAVS–IRF3 signaling pathway. Concurrently, CHAF1A preserved genomic stability, limiting the release of double-stranded DNA and activation of the cGAS–STING pathway. Loss of CHAF1A potentiated the response to immunotherapy through the coordinated activation of these dual pathways. We then performed a small-molecule compound screen and identified a CHAF1A inhibitor, baimaside, which enhanced the effect of anti–PD-1 therapy to augment antitumor immunity. Collectively, these data indicate that CHAF1A represents a potential therapeutic target for sensitizing ESCC to immunotherapy and provide a potential combination strategy for reversing immunotherapy resistance.