Review: Immune Gene Regulation via cGAS-STING in ARID1A-deficient cancers and their response to therapeutic stress

ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, plays a crucial role in maintaining genomic stability by facilitating DNA double-strand break (DSB) repair through chromatin loop formation and transcriptional regulation. Its deficiency is frequently observed in various cancers and is associated with impaired DNA repair mechanisms and increased accumulation of cytosolic DNA. This triggers the activation of the CGAS-STING pathway, a cytosolic DNA-sensing mechanism that induces type I interferon (IFN-I) responses and expression of interferon-stimulated genes (ISGs) such as IFIT1, ISG15, CXCL9, CXCL10, and CCL5. These immune modulators enhance antitumor immunity by promoting immune cell infiltration into the tumor microenvironment. Experimental studies using ARID1A-deficient cancer cell lines—including MDA-MB-231 and AID-Diva—demonstrated increased expression of IFN-α, IL-6, and chemokines upon DNA damage, confirming CGAS-STING pathway activation. Clinically, these downstream genes serve as potential biomarkers for predicting response to DNA-damaging agents and immune checkpoint inhibitors. The findings support the potential of targeting DNA damage-induced innate immune signaling to enhance therapeutic efficacy in ARID1A-deficient tumors.