Fig. 8

Mechanisms and clinical manifestations of CAR-T and GVHD-associated CRS. CAR-T: Following infusion, CAR-T cells are transported to the tumor site, where target recognition activates them to proliferate locally and produce cytokines such as IL-6, IFN-γ, GM-CSF, and TNF, along with soluble inflammatory mediators and catecholamines. This activation stimulates various components within the tumor microenvironment, leading to increased cytokine levels in peripheral blood and further expansion of the CAR-T cell population. The resulting cytokine storm can trigger systemic inflammation, potentially leading to multi-organ dysfunction. GVHD: Conditioning chemotherapy or radiation causes tissue damage, releasing pathogen-associated molecular patterns (PAMPs; e.g., LPS) and damage-associated molecular patterns (DAMPs; e.g., from total body irradiation, TBI), which increase the activation of host APCs during the initiation phase. In the donor T cell activation phase, these host APCs activate alloreactive donor CD4⁺ and CD8⁺ T cells. In the effector phase, effector T cells and pro-inflammatory cytokines damage epithelial cells of the skin, gastrointestinal (GI) tract, liver, CNS, kidneys, and lungs, leading to apoptosis and necroptosis, and resulting in the symptoms of aGVHD. Abbreviation: CAR-T chimeric antigen receptor-modified T cells, GM-CSF granulocyte-macrophage colony-stimulating factor, IFN interferon, MIP macrophage inflammatory protein, aGVHD acute graft-versus-host disease, APCs antigen presenting cells. The figure was created with the assistance of Adobe Illustrator