ARID1A Mediates SWI/SNF-Independent Maintenance of Heterochromatin Architecture to Restrain Viral Mimicry and Immunogenicity in Colon Cancer

ARID1A is a crucial subunit of the SWI/SNF chromatin-remodeling complex and is frequently mutated in human cancers. While its tumor-suppressive activity has been ascribed exclusively to SWI/SNF-dependent chromatin remodeling, we established here a SWI/SNF-independent role of ARID1A in safeguarding heterochromatin architecture to silence viral mimicry and restrain immunogenicity in colorectal cancer. ARID1A deficiency triggered viral mimicry and enhanced immunogenicity in both microsatellite stable and instable contexts. Mechanistically, ARID1A interacted with TRIM28 to preserve heterochromatin rigidity. Loss of ARID1A displaced SETDB1 from the TRIM28-containing heterochromatin complex, leading to the reversal of H3K9me3-mediated repression at endogenous retroelement regions. The release of these elements triggered viral mimicry, exemplified by enhanced type I interferon-mediated immune responses. Notably, disrupting the ARID1A-TRIM28 interaction with synthetic peptides induced a viral mimicry phenotype in ARID1A wildtype tumors, converting immunologically "cold" lesions into T-cell-inflamed microenvironments and suppressing tumor growth. Both cytosolic RNA and DNA sensors were required for the ensuing interferon response and for the heightened sensitivity to PD-1 blockade elicited by ARID1A deficiency. These findings thus reveal an unanticipated heterochromatin gatekeeper function of ARID1A that operates outside the SWI/SNF complex and can be exploited to potentiate immune checkpoint therapy activity.