{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:04:48Z","timestamp":1784009088976,"version":"3.55.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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-1\u03b2\u2013IL-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-\u03baB\/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 \u201carmoured\u201d CAR-T-cells equipped with inducible regulatory circuits may improve the safety and efficacy of cellular immunotherapies in multiple myeloma.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1882156","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:37:47Z","timestamp":1784007467000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The regulatory role of IL-37 and IL-38 in CAR-T associated cytokine release syndrome in multiple myeloma"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiujuan","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Hematology, Shaanxi Provincial People\u2019s Hospital","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Emergency 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