Table 1 Regulatory effects of systemic metabolites on immune cells and stromal cells in the TME
From: Cancer cachexia: molecular basis and therapeutic advances
Cell types | Metabolites | Cellular functions | Major Mechanisms | References |
|---|---|---|---|---|
Macrophages | Lactate | Promote M2 macrophage transition; drive expression of M2-like genes during M1 macrophage polarization | Enhancing H3K9ac of M2-associated gene; promoting histone lysine lactylation | |
Pyruvate | Upregulate PD-L1 in TAMs; reduce infiltration of CD45+ immune cells, cytotoxic T cells, and NK cells | Intervening PC under hypoxic conditions | ||
Alpha -ketoglutarate | Activate M2 phenotype and suppress proinflammatory cytokine production | Activating mTORC1 signaling | ||
Glutamine | Enhance M2 polarization and CCL22 secretion; repress TNF production, lysosomal function, and antigen presentation | Maintaining TCA cycle activity; inhibiting the NF-κB, and enhancing STAT3 signaling | ||
ω-3 PUFA | Reduce COX-2 expression and PGE2 synthesis; inhibit the secretions of TNF-α and IL-6 | Inhibiting the phosphorylations of IKKβ and JNK, preventing IκB degradation; repressing TLR4 signaling via Akt/JNK phosphorylation and the nuclear translocation of p65 | ||
MCFAs | Enhance inflammatory responses and macrophage phagocytosis | Activating GPR84 signaling | ||
CD4+ T cells | Alpha -ketoglutarate | Attenuate FoxP3+ Treg differentiation and increase inflammatory cytokines (e.g., TNF, GM-CSF, IFN-γ, and IL-17A) | Increasing fatty acid synthesis, triacylglycerol stores, and OXPHOS | |
Methionine | Induce differentiation; secrete higher levels of IFN-γ | Generating methyl donors to sustain RNA, protein, and DNA synthesis | ||
SCFA | Promote IL-22 production that protects intestines from inflammation | Increasing the accessibility of HIF1α-binding sites in the Il22 promoter through histone modification | ||
CD8+ T cells | Lactate | Promote cell stemness and efficacy of anti-PD-1 therapy; diminish IFN-γ production | Enhancing H3K27ac of the Tcf7; disturbing glycolysis and NFAT translocation | |
Pyruvate | Reduce cytotoxicity; support CD8+ T-cell antitumor function | Inhibiting autocrine signaling through SUCNR1 by reducing PC activity; MPC facilitates nutritional metabolism | ||
Alpha -ketoglutarate | Increase infiltration of IFNγ + CD8 + T cells | Activating STAT1 to promote PD-L1 expression | ||
Ketone bodies | Enhance metabolism of CD8+ T cells; increase production of inflammatory cytokines; enhance anti-tumor immunity | Increasing permissive H3K27Ac at effector gene loci (e.g., Ifng, Gzmb, Tbx21); promoting the synthesis of TCA cycle | ||
NK cells | Lactate | Diminish IFN-γ production | Disturbing glycolysis and NFAT translocation | |
ω-3 PUFA | Increase cytotoxicity and IFN-γ production | Promoting mitochondrial OXPHOS activity by regulating PGC-1α expression | ||
T cells | Arginine | Promote T-cell proliferation and cytokines production such as IFN-γ, IL-5, and IL-10 | Facilitating the synthesis of CD3ζ or other components of the TCR | |
Glutathione | T-cell activation and proliferation; Th17 development and Th17-driven CNS inflammation | Producing GSH and suppressing ROS upon TCR stimulation | ||
MDSCs | Glutamine | Increase generation and recruitment of MDSCs | Increasing active caspase-3 on MDSCs and CSF3 expression in tumor cells. | |
Dendritic cells | Alpha -ketoglutarate | Promote activation of DC; increase proinflammatory cytokines CCL5 and CXCL10 | Reducing autophagy in tumor cells | |
ω-6 PUFA | Inhibit differentiation and maturation | Skewing dendritic cell metabolism toward glycolysis and reducing immune stimulation | ||
Fibroblasts | Lactate | Stimulate CAF phenotype | Downregulating p62 transcriptionally | |
Ketone bodies | Inhibit CAF proliferation and increase NK and cytotoxic T-cell infiltration | Suppressing CXCL12 expression in CAFs and CXCL12/CXCR4/CXCR7 signaling in tumor cells | ||
Endothelial cells | ω-3 PUFA | Enhance anticancer drug delivery efficiency | Disrupting the NO signaling cascades, lowering IFP |
