Elevated CHAF1A suppresses type I interferon production and causes immunotherapy resistance in esophageal squamous cell carcinoma.

Authors

Yue Ma, Mengde Shi, Ming Ma, Siru Li, Nana Cui, Yingjue Li, Tianjiao Dang, Rui Yang, Yang Bai, Bojun Wang, Chunhui Zhang, Chao Liu, Yanqiao Zhang

Published in

Cancer immunology research. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

In esophageal squamous cell carcinoma (ESCC), chemoradiotherapy potentiates the effects of immune checkpoint inhibitors (ICIs) 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 multi-omic 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 (ERVs). This suppression prevented the accumulation of double-stranded RNA (dsRNA) and the subsequent activation of the MAVS-IRF3 signaling pathway. Concurrently, CHAF1A preserved genomic stability, limiting the release of double-stranded DNA (dsDNA) 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.

PMID:
42462139
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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