Running on Empty Signals: What Human MALT1 Deficiency Reveals About Immune Control.

Human genetic disorders affecting intracellular signaling pathways provide an unparalleled opportunity to understand how immune responses are regulated in vivo. Among these conditions, MALT1 deficiency has emerged as a particularly informative model because it reveals how subtle quantitative changes in antigen receptor signaling can translate into profound clinical consequences. As a central component of the CARD11-BCL10-MALT1 (CBM) signalosome, MALT1 integrates receptor-derived signals and determines whether downstream nuclear factor kappa B (NF-kB) activation reaches thresholds required for effective immune responses. Rather than representing a single, uniform loss-of-function condition, MALT1 deficiency is genetically and functionally heterogeneous: different pathogenic variants affect MALT1 protein expression, paracaspase/protease activity, or its scaffolding role within the CBM complex to varying degrees, and these differences determine whether the predominant phenotype reflects impaired immune activation, immune dysregulation, or a combination of both. This functional diversity helps explain why patients with MALT1 deficiency may present with recurrent infections, inflammatory features, regulatory T-cell defects, and progressive impairment of B-cell immunity, either alone or in combination. In this review, we discuss how insights from human disease, experimental models, and therapeutic studies converge to position MALT1 as a critical regulator of immune homeostasis and explore broader implications for translational immunology. Due to the rarity of MALT1 deficiency, we carefully compiled and contextualized the few reported cases of hematopoietic stem cell transplantation (HSCT), highlighting emerging translational patterns.