Fig. 3

The biological mechanism of chronic stress affecting immune cells. A NK cell: E/NE inhibits cytokines production, including IL-12, IFN-γ and IL-2, through DNA-dependent mechanisms activation and protein synthesis. B Dendritic cell: chronic stress downregulates maturation-related markers such as CD40, CD68, and MHC II receptors in DCs. GRs upregulate TSC22D3 expression, mediate immunosuppressive effects through NF-κB, Ras and CVEBP, reduce pro-inflammatory cytokines IL-6, 12, and 23 productions, and block antigen presentation, resulting in the inability of TILs to acquire mature phenotype, as evidenced by low KLRG-1. C TAM & MDSC: chronic stress mediates metabolic reprogramming of macrophages and promotes immunosuppression. β2-ARs increases oxidative phosphorylation and promotes CPT1A expression; β2-ARs also increases FAO, which increases PGE2 production through COX2 overexpression and inhibits IFN-γ production by CD8⁺ T cells. GCs-GRs inhibit LRP1 and increase SIRPα, leading to an imbalance in the LRP1/SIRPα axis and inhibiting the phagocytosis of tumor cells by macrophages. D TIL: chronic stress reshaped the TIL phenotype in the TME, CD4+ TIL exhibit PD-1⁺, FOXP3⁺, CD8⁺ TIL exhibit PD-1⁺, TIM3⁺, Lag3⁺, IFN-γ⁻, CD28⁻. β2-ARs decreased GLUT1 and glucose uptake, resulting in reduced glycolysis and oxidative phosphorylation. GCs-GRs induce GILZ expression, which synergistically induces FoxP3 expression with TGF-β and SMAD2/3/4, further enhancing TGF-β signaling and promoting the conversion of naive T cells to Treg cells. Treg cells can produce immunosuppressive cytokines, including IL-10 and IL-35