Targeting BLVRB Overcomes Immunosuppression and Potentiates Immunotherapy in Monocytic Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) is characterized by significant immunosuppression, limiting the efficacy of immunotherapy. Monocytic AML presents unique immunosuppressive features and constitutes a challenging subtype, necessitating focused investigation. Using single-cell multiomic analyses of primary AML samples, we revealed the immunosuppression landscape of monocytic AML and identified biliverdin reductase B (BLVRB) as a marker of immunosuppressive monocytic AML cells. BLVRB depletion downregulated immunomodulatory gene expression and sensitized AML cells to T-cell cytotoxicity, resulting in improved therapeutic efficacy in cell line–derived xenograft (CDX) and patient-derived xenograft (PDX) models. Mechanistically, BLVRB signals through the transcription factor MAFB to promote the expression of various immunosuppression-associated genes, resulting in inhibitory effects against anti-AML T cells. We further demonstrated that the small-molecule tamibarotene targets BLVRB, enhancing the efficacy of both chimeric antigen receptor (CAR) T and anti–PD-1 antibody therapies in AML. These findings elucidate the critical mechanism regulating immunosuppression in monocytic AML and identify BLVRB as a therapeutic target for improving AML immunotherapy. Significance: We revealed the particularly immunosuppressive feature of the monocytic AML subset and identified BLVRB-targeting strategies to reverse AML immunosuppression. Genetic disruption or pharmacologic inhibition of BLVRB sensitized AML cells to T cell–mediated cytotoxicity, offering potential strategies to enhance the therapeutic potency of immunotherapy against AML.