ARID1A mutation is associated with an immunosuppressive microenvironment and poor prognosis in hepatocellular...

Identifying recurrent genetic mutations is crucial for advancing the understanding and treatment of hepatocellular carcinoma (HCC). The chromatin regulator ARID1A is frequently mutated in cancers, but its integrated impact on prognosis and the tumor immune microenvironment (TIME) in HCC is unclear.

Somatic mutation and transcriptome data from TCGA and ICGC databases were analyzed. Associations with tumor mutation burden (TMB) and prognosis were evaluated. Immune infiltration was estimated using CIBERSORT/ssGSEA. Pathway and immunomodulator analyses were performed. ARID1A expression was validated via tissue microarray and an independent cohort (GSE76427).

Among 19 commonly mutated genes, ARID1A mutation was an independent prognostic factor for poorer overall survival and was associated with higher TMB. A nomogram integrating ARID1A status, TMB, and stage showed good predictive accuracy. ARID1A mRNA/protein was upregulated in HCC tissues, correlating with advanced stage. ARID1A-mutant tumors exhibited distinct pathway enrichments (e.g., p53 signaling, drug metabolism). The ARID1A-mutant TIME was characterized by an increased proportion of naive CD4⁺ T cells and significantly elevated expression of specific immunomodulators, including the immunosuppressive molecules IDO1 and BTLA. Correlation analysis further linked this molecular signature to the specific immune cell landscape, suggesting an "inflamed but suppressed" TME.

ARID1A mutation defines an aggressive HCC subtype characterized by high TMB coupled with a distinct immunosuppressive TIME. These findings suggest ARID1A status has prognostic value and may inform combination immunotherapy strategies, such as targeting IDO1 or BTLA, warranting further clinical and mechanistic validation.