ARID1B mutations promote immune evasion in acute myeloid leukemia through upregulating VISTA expression.

Acute myeloid leukemia (AML) is defined by epigenetic heterogeneity, and recurrent mutations in chromatin remodelers are associated with a poor prognosis. Whether these mutations drive treatment resistance through remodeling of the tumor immune microenvironment remains unclear. ARID1B, a recurrently mutated SWI/SNF subunit in AML, has an uncertain association with adverse outcomes, and its immunomodulatory role remains undefined. This study characterized the clinical, genomic, and immunological features of ARID1B-mutant AML and assessed their impact on treatment response and prognosis. ARID1B mutations displayed clinical heterogeneity. Patients harboring the p.Gly332_Ala336del variant achieved significantly higher rates of complete remission and overall response to induction chemotherapy compared with those carrying other ARID1B mutations. Prognostic impact was context-dependent: ARID1B mutation conferred inferior survival specifically in acute promyelocytic leukemia and in patients aged ≥65 years. Mechanistically, ARID1B mutations were associated with an immunosuppressive microenvironment, characterized by upregulated VISTA expression on leukemic blasts, reduced bone marrow CD8+ T-cell infiltration, and impaired effector function of both CD8+ T cells and NK cells. These findings suggest that ARID1B mutations in AML have dual implications: the p.Gly332_Ala336del variant enhances chemosensitivity, while ARID1B dysfunction broadly facilitates an immune- evasive phenotype, likely through VISTA-mediated suppression. This study identifies ARID1B mutation as a conditional prognostic marker and a correlate of the AML immune landscape, thereby supporting mutation-subtype-specific management and therapeutic targeting of the VISTA pathway.