Table 1 Metabolites and their effects on APC function.

From: Metabolic guidance and stress in tumors modulate antigen-presenting cells

TME metabolic products/metabolites

Effect on APCs and immune consequences

Mechanism of APC tolerance

Reference

Low pH

Favor moDC differentiation;

Obstruct antigen uptake and destabilize antigen-MHCI complex

Increase mitochondrial respiration; Inhibit mTORC1 activity; DEC205 conformational change

[77, 83, 84]

WNT5a

Decreased CD103+DCs infiltration;

IDO1 production; Treg generation

β-catenin activation

[72, 136]

Promote FAO process

PPARγ upregulates the expression of CPT1A

[72]

Prostaglandin E2

Production of IL-6, CXCL1 and G-CSF; Type I IFN elimination

?

[137]

Hypoxia

Short-time: moDCs have a better migration;

Long-time: IDO and adenosine (DCs)

VEGF and differentiation into M2 TAMs

Long-time - HIF1α expressing; lncRNA-Dpf3

[52, 58]

Angiogenesis and fine-tunes M2 phenotype

Upregulate REDD1

[54, 55]

Vasculatures

ANG2/TIE2 axis

[57]

Glucosylceramide

M2 polarization

ER stress

[63]

Lipid

Pro-tumoral properties

Caspase-1

[64]

Utilize for FAO

PPAR and CD36 expressing

[62, 65]

Downregulate CD86 and upregulate IL-10

?

[76]

ox-tr-LB

Reduced antigen processing ability; Impair CD8 T cell response

ox-tr-LB covalently adduct with Hsp70

[75]

Fatty acid-carrying TDEs

DCs intracellular lipid content and mitochondrial respiration

Upregulate PPARα signaling pathway, promotes FAO, and enriches lipid droplets

 

TME

Lipid body accumulation;

Antigen presentation

ROS/4-HNE adducts/ER stress/XBP1

[71, 73]

Lactate

M2 polarization

Upregulate M2-associated genes (e.g., Arg1 and VegfA); Olfr78/GPCR/ICER;

Epigenetic modulator

[58, 78, 80, 81]

Lactate

Decrease MHCII, cAMP, IL-6, and IL-12

GPR81 expression (DC)

[82]

Succinate

Migration of TAMs into TME

PI3K/HIF1α cascade

[85]

Glutaminolysis

Alternative activation of macrophages

Jumonji-domain-containing protein-3

[67]

2-HG

M2 polarization; T cell dysfunction via CD39 expression

Kynurenine/AhR/NF-κB/KLF4 cascade

[11, 88]

  1. Overview of TME metabolites reprogram APCs to elicit APC-mediated anti- or pro-cancer immunity.
  2. IDO1 indoleamine 2,3-dioxygenase, FAO fatty acid oxidation, PPARγ peroxisome proliferator-activated receptor-γ, CPT1A carnitine palmitoyltransferase-1a, HIF1α hypoxia-inducible factor 1α, VEGF vascular endothelial growth factor, REDD1 regulated in development and DNA damage response 1, ANG2 angiopoietin 2, ER endoplasmic reticulum, Ox-tr-LB oxidatively truncated lipids, TDE tumor-derived exosomes, 2-HG 2-hydroxyglutarate, AhR aryl hydrocarbon receptor, KLF4 kruppel-like factor 4, ? unknown.
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