AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?

Abstract

Immunotherapy has now garnered significant attention as an essential component in cancer therapy during this new era. However, due to immune tolerance, immunosuppressive environment, tumor heterogeneity, immune escape, and other factors, the efficacy of tumor immunotherapy has been limited with its application to very small population size. Energy metabolism not only affects tumor progression but also plays a crucial role in immune escape. Tumor cells are more metabolically active and need more energy and nutrients to maintain their growth, which causes the surrounding immune cells to lack glucose, oxygen, and other nutrients, with the result of decreased immune cell activity and increased immunosuppressive cells. On the other hand, immune cells need to utilize multiple metabolic pathways, for instance, cellular respiration, and oxidative phosphorylation pathways to maintain their activity and normal function. Studies have shown that there is a significant difference in the energy expenditure of immune cells in the resting and activated states. Notably, competitive uptake of glucose is the main cause of impaired T cell function. Conversely, glutamine competition often affects the activation of most immune cells and the transformation of CD4⁺T cells into inflammatory subtypes. Excessive metabolite lactate often impairs the function of NK cells. Furthermore, the metabolite PGE2 also often inhibits the immune response by inhibiting Th1 differentiation, B cell function, and T cell activation. Additionally, the transformation of tumor-suppressive M1 macrophages into cancer-promoting M2 macrophages is influenced by energy metabolism. Therefore, energy metabolism is a vital factor and component involved in the reconstruction of the tumor immune microenvironment. Noteworthy and vital is that not only does the metabolic program of tumor cells affect the antigen presentation and recognition of immune cells, but also the metabolic program of immune cells affects their own functions, ultimately leading to changes in tumor immune function. Metabolic intervention can not only improve the response of immune cells to tumors, but also increase the immunogenicity of tumors, thereby expanding the population who benefit from immunotherapy. Consequently, identifying metabolic crosstalk molecules that link tumor energy metabolism and immune microenvironment would be a promising anti-tumor immune strategy. AMPK (AMP-activated protein kinase) is a ubiquitous serine/threonine kinase in eukaryotes, serving as the central regulator of metabolic pathways. The sequential activation of AMPK and its associated signaling cascades profoundly impacts the dynamic alterations in tumor cell bioenergetics. By modulating energy metabolism and inflammatory responses, AMPK exerts significant influence on tumor cell development, while also playing a pivotal role in tumor immunotherapy by regulating immune cell activity and function. Furthermore, AMPK-mediated inflammatory response facilitates the recruitment of immune cells to the tumor microenvironment (TIME), thereby impeding tumorigenesis, progression, and metastasis. AMPK, as the link between cell energy homeostasis, tumor bioenergetics, and anti-tumor immunity, will have a significant impact on the treatment and management of oncology patients. That being summarized, the main objective of this review is to pinpoint the efficacy of tumor immunotherapy by regulating the energy metabolism of the tumor immune microenvironment and to provide guidance for the development of new immunotherapy strategies.

Fig. 1. Bidirectional regulation mechanism of AMPK at TIME.

AMPK exerts bidirectional regulation in the tumor immune microenvironment, impacting not only tumor cells but also immune cells. For instance, T cells are subjected to glucose uptake and utilization by T cell, ATP of T cell, GZB and T cell cycle and proliferation to suppress tumors and anaerobic glcolysis of T cell, pyruvate secretion by the T cell, lactic acid secretion by T cell, autophapy and growth of T cell to promote tumorigenesis. Macrophages undergo Akt-HIF 1α-mTOR pathway, polarization toward the M1 subtype, pyruvate and lactic acid build up for tumor inhibition, and IL-10, IGF-β for tumor promotion. B cells exhibit tumor suppression with mitochondrial homeostasis of B cell, B cell glycolysis pathway, glucose transport in B cell, mitochondrial respiration of B cell and promotion with ATP of tumor cell, FAS in tumor cell, FAO in tumor cell, NADPH of tumor cell. NK cells inhibit tumors through mTOR pathway, phosphorylated MAT, the ability of NK cells to cross tissue blood vessels while promoting tumorigenesis via SM and surface film projection.

Fig. 2. Structure, function, and main regulatory factors of AMPK.

AMPK is comprised of three subunits, namely α, β, and γ. It can be activated by CAMKK2, which is regulated by Ca2⁺ concentration, as well as by LKB1, consisting of STRAD, MO25, and LKB1. Additionally, AMPK can be activated by compounds, such as Salicylate and A-769662, or factors that increase AMP levels, including AMP analogues like AICAR, exercise, energy stress such as glucose deficiency, and drugs like aspirin or compounds such as metformin. The primary functions of AMPK are to promote the ATP synthesis process (FAO, glycolysis, glucose uptake, etc.), inhibit the ATP decomposition process (such as protein synthesis, lipid synthesis, gluconeogenesis, etc.), regulate mitochondrial homeostasis, and promote autophagy. AMPK AMP-activated protein kinaseST, PI3K phosphoinositide 3-kinase, CAMKK2 recombinant calcium/calmodulin-dependent protein kinase kinase 2, MO25 mouse protein-25, LKB1 Liver kinase B1, mTOR mammalian target of rapamycin, FBP fructose 1,6-bisphosphatase, ATM Ataxia Telangiectasia Mutated, BD binding domain, CBM carbohydrate-binding module, CBS Cystathionine Beta-Synthase, ATP adenosine 5’-triphosphate, ADP adenosine diphosphate, AMP adenosine monophosphate, CCCP Carbonyl cyanide 3-chlorophenylhydrazone, EMT Epithelial-mesenchymal transition, ATG9 autophagy-related protein 9, ULK1 Unc-51-like kinase, PGC1 peroxisome proliferator activating receptor C-coactivator 1, ERRs Estrogen-related receptors, PPARr peroxisome proliferators-activated receptors, MFF MAC-Forced Forwarding, DRP1 dynamin-related protein 1.

Fig. 3. The regulation of AMPK on energy metabolism, mitochondrial homeostasis, and autophagy.

AMPK activation regulates a variety of energy metabolic pathways. Green arrows represent up-regulated processes while red blockers represent down-regulated processes. Text in green font indicates biological processes that are mainly upregulated by AMPK, while text in red font indicates biological processes that are mainly downregulated by AMPK. These processes can be classified into glucose metabolism, lipid metabolism, protein metabolism, mitochondrial homeostasis, autophagy, and ribosome regulation. It is evident that AMPK plays a central role in energy metabolism and oxidative metabolism. AMPK AMP-activated protein kinase, GFAT1 Glutamine fructose-6-phosphate amidotransferase 1, HSL hormone-sensitive triglyceride lipase, ATGL adipose triglyceride lipase, CD36 Platelet glycoprotein 4, ACC2 acetyl-CoA carboxylase 2, mTORC1: mechanistic target of rapamycin complex1, ATM Ataxia Telangiectasia Mutated, P53 Cellular tumor antigen p53, eEF2K Eukaryotic extension factor 2 kinase, TSC TSC Complex Subunit 1, S6K1 Ribosomal S6 kinase 1, EIF4E eukaryotic initiation factor 4E, ULK1 Unc-51-like kinase, PPAR peroxisome proliferators-activated, GC1 Glume Coverage 1, TFAM Transcription Factor A, Mitochondrial, TIF1A Transcription Intermediary Factor 1-Alpha, HNF4α hepatocyte nuclear factor 4alpha, SIRT1 Silent Mating Type Information Regulation 2 Homolog 1, NAD nicotinamide adenine dinucleotide, H2B: histone 2 B, CREB: cyclic-AMP response binding protein, HDAC histone deacetylase, MLC2 Myosin Light Chain 2, VEGF vascular endothelial growth factor, eNOS endothelial nitric oxide synthase, FAS fatty acid synthesis, TBC1D1 Tre-2/BUB2/cdc 1 domain family 1, GEF GMP exchange factor, MEF2 myocyte enhancer factor-2, PLD1 Phospholipase D1, GLUT Glucose Transporter, TXNIP thioredoxin-interactingprotein, PFKFB3 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3, PFK1 Phosphofructokinase-1, HIF-1α Transcription Intermediary Factor 1-Alpha, GS Glutamine synthetase, GP Glycogen phosphorylase.