The role of cytokines in cytokine release syndrome (CRS) after CAR T cell therapy

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for hematological malignancies. However, cytokine release syndrome (CRS) remains a common and potentially severe toxicity, significantly affecting patient safety and requiring intensive clinical management. This review provides a focused synthesis on the role of cytokines in CRS after CAR T cell therapy, integrating recent mechanistic insights with clinical implications. We delineate the cellular and molecular pathways involving key cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), describing their sources, downstream signaling events, and effects on target tissues. By bridging basic cytokine biology with clinical aspects and therapeutic strategies, this review aims to provide a comprehensive framework for understanding the role of cytokines in CRS pathophysiology, ultimately supporting the development of safer and more effective CAR T cell therapies. • Framework linking cytokine biology to clinical features of CAR-T derived CRS • Mechanistic cytokine-by-cytokine analysis of sources, signaling, and tissue effects • Coparison of cytokine-directed therapies and other treatment strategies