Halting multiple myeloma with MALT1 inhibition: suppressing BCMA-induced NF-κB and inducing immunogenic cell death

Abstract Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 μM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.