The regulatory role of IL-37 and IL-38 in CAR-T associated cytokine release syndrome in multiple myeloma.

Multiple myeloma remains largely incurable despite advances in proteasome inhibitors and monoclonal antibodies. Chimeric antigen receptor (CAR)-T-cell therapy targeting B-cell maturation antigen (BCMA) has achieved deep responses in relapsed/refractory multiple myeloma; however, its clinical utility is constrained by cytokine release syndrome (CRS). CRS is a multicellular hyperinflammatory process driven by CAR-T-derived cytokines, monocyte/macrophage activation, and amplification of the IL-1β-IL-6 axis, leading to endothelial dysfunction and metabolic reprogramming. While IL-6 blockade is the standard of care, severe CRS often persists due to redundant upstream inflammatory signalling. This mini-review evaluates the emerging roles of IL-37 and IL-38, anti-inflammatory members of the IL-1 superfamily, as endogenous regulators of CAR-T-associated hyperinflammation. IL-37 functions primarily as a systemic mediator that suppresses NF-κB/MAPK signalling, inflammasome activity, and endothelial injury. In contrast, IL-38 acts as a tissue-resident regulator that restrains early innate immune priming and modulates macrophage-dendritic cell interactions within the bone marrow microenvironment. We propose a phase-dependent regulatory axis wherein IL-38 limits inflammatory initiation while IL-37 suppresses systemic amplification during peak CRS. These pathways represent promising immunoregulatory checkpoints with translational potential as biomarkers and therapeutic targets. Leveraging these cytokines through recombinant proteins or "armoured" CAR-T-cells equipped with inducible regulatory circuits may improve the safety and efficacy of cellular immunotherapies in multiple myeloma.