Unveiling tumor immune evasion mechanisms: abnormal expression of transporters on immune cells in the tumor microenvironment

Abstract

The tumor microenvironment (TME) is a crucial driving factor for tumor progression and it can hinder the body's immune response by altering the metabolic activity of immune cells. Both tumor and immune cells maintain their proliferative characteristics and physiological functions through transporter-mediated regulation of nutrient acquisition and metabolite efflux. Transporters also play an important role in modulating immune responses in the TME. In this review, we outline the metabolic characteristics of the TME and systematically elaborate on the effects of abundant metabolites on immune cell function and transporter expression. We also discuss the mechanism of tumor immune escape due to transporter dysfunction. Finally, we introduce some transporter-targeted antitumor therapeutic strategies, with the aim of providing new insights into the development of antitumor drugs and rational drug usage for clinical cancer therapy.

Keywords: cancer therapy; metabolites; the tumor microenvironment; transporters; tumor immune evasion.

Figure 1

Transmembrane transportation of lipids. Transmembrane transport of lipids is mediated by various transport proteins. FATPs and CD36 are mainly responsible for mediating exogenous FA uptake. LDL and VLDL can also achieve intracellular transport through CD36, and then hydrolyzed by LAL into FA. Intracellular FA can be transported to different organelles or compartments for subsequent local lipid metabolism by FABPs, or excreted by ABC transporters. Fatty acid (FA), The fatty acid transporter family (FATPs), The fatty acid binding proteins (FABPs), Lysosomal acidic lipase (LAL), Low-density lipoprotein (LDL), Very low-density lipoprotein (VLDL).

Figure 2

Expression of amino acid transporters in tumor and immune cells and their substrates. Some amino acids and their transporters are engaged in the regulation of the immune responses in the tumor microenvironment. Examples we mentioned are depicted in the figure. Arginine (Arg), Cysteine (Cys), Cystine (Cys-Cys), Glutamate (Glu), Glutamine (Gln), Kynurenine (Kyn), Leucine (Leu), Methionine (Met), Tryptophan (Trp).

Figure 3

Transporter-targeted antitumor drugs. Current approaches including chemical drugs and antibodies for transporter-targeted antitumor drugs. (A) Lipid and glucose transporters-targeted drugs. (B) Lactate, amio acid and nucleoside transporters-targeted drugs.