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

UNLABELLED: AT-rich interaction domain 1A (ARID1A) is a crucial subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex and the ARID1A gene is frequently mutated in human cancers. Although its tumor-suppressive activity has been ascribed exclusively to SWI/SNF-dependent chromatin remodeling, we established in this study 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 protein 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 IFN-mediated immune responses. Notably, disrupting the ARID1A-TRIM28 interaction with synthetic peptides induced a viral mimicry phenotype in ARID1A wild-type 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 IFN 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.

SIGNIFICANCE: Loss of ARID1A disrupts heterochromatin architecture and induces viral mimicry and immunogenicity in a TRIM28-dependent but SWI/SNF-independent manner, highlighting the potential of targeting the ARID1A-TRIM28 axis to improve immunotherapy efficacy.