Can Metabolic Interventions Enhance the Efficacy of Cancer Immunotherapy?

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Can Metabolic Interventions Enhance the Efficacy of Cancer Immunotherapy?

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Can Metabolic Interventions Enhance the Efficacy of Cancer Immunotherapy?

Increasing evidence suggests that cancer metabolism not only plays a crucial role in the signaling pathways that sustain cancer growth and survival but also holds broader significance in regulating anti-tumor immune responses through the release of metabolites and influencing the expression of immune molecules such as lactate, PGE2, and arginine.

In fact, this energetic interplay between tumor and immune cells results in metabolic competition within the tumor ecosystem, limiting the availability of nutrients and leading to an acidic microenvironment that hampers immune cell function.

Interestingly, metabolic reprogramming is also indispensable in various immune cell processes for maintaining their own and the body’s homeostasis.

Current research increasingly indicates that immune cells undergo metabolic reprogramming during proliferation, differentiation, and execution of effector functions, which is vital for immune responses.

Metabolism involves the biochemical network of converting nutrients into small molecules called metabolites.

Under aerobic conditions, normal cells primarily obtain energy through glycolysis in the cytoplasm, followed by oxidative phosphorylation (OXPHOS) in the mitochondria.

When oxygen is scarce, cells rely on glycolysis, a non-oxygen-consuming metabolic pathway, to provide energy. However, the metabolic pattern of cancer cells is distinct from normal cells.

Known as the “Warburg effect,” cancer cells preferentially utilize glycolysis in the cytoplasm even in the presence of oxygen, perhaps due to the need for rapid energy supply for their uncontrolled proliferation, as glycolysis generates ATP much faster than oxidative phosphorylation, albeit with a lower ATP yield per glucose molecule.

More importantly, cancer cells can suppress anti-tumor immune responses by competing for and consuming essential nutrients or otherwise compromising the metabolic adaptability of infiltrating immune cells. Immune cells, in fact, can sense various signals in the microenvironment and tailor specific immune functions accordingly.

Mounting evidence suggests that immune responses are closely tied to significant alterations in tissue metabolism, including nutrient consumption, increased oxygen consumption, and the generation of reactive nitrogen and oxygen intermediates.

Similarly, many metabolites within the tumor microenvironment also influence the differentiation and effector functions of immune cells.

However, recent studies indicate that immune cells compete for nutrients with cancer cells and other proliferating cells in the microenvironment.

This suggests that metabolic interventions hold promise for enhancing the effectiveness of immunotherapy.

Metabolism of Tumor Cells:

Metabolic reprogramming, involving adjustments to energy metabolism to promote rapid cell growth and proliferation, has long been considered a hallmark of cancer. Because cancer is a heterogeneous disease, it exhibits diverse metabolic patterns owing to variations in cell types and structures. In fact, cancer cells primarily rely on the glycolytic pathway to rapidly provide ATP for their own growth while also supplying biosynthetic intermediates for cell replication via the pentose phosphate pathway (PPP) and serine metabolism. Interestingly, cancer cells choose different metabolic pathways to generate ATP and biomolecules for their growth based on external nutrient concentrations and stress conditions. Their metabolic pattern is complex and variable, allowing them to adapt to the best metabolic mode for survival in different environments (as illustrated in Figure 1).

Figure 1: Oncogenic factors modulate cancer cell metabolism.

Immune Cell Metabolism:

Energy utilization varies significantly between immune cells in resting and activated states.

Among the various immune cells with distinct functions, T cells play a crucial role in clearing pathogens and killing cancer cells.

Different T cell activation states exhibit distinct metabolic patterns. For instance, naive T cells primarily rely on OXPHOS to produce ATP, and their metabolism is relatively static.

Upon external stimulation, effector T cells (Teff) transition to a metabolic activation state, increasing nutrient uptake, glycolysis rates, and the accumulation of proteins, lipids, and nucleotides.

Simultaneously, mitochondrial oxygen consumption decreases, granting Teff cells the ability to grow, proliferate, and generate effector offspring cells for executing cytotoxic functions. Activated neutrophils, M1 macrophages, and dendritic cells expressing inducible nitric oxide synthase (iNOS) predominantly depend on glycolysis for energy.

Glycolysis plays a crucial role in the activation of dendritic cells; however, dendritic cells primarily utilize oxidative phosphorylation for energy metabolism in a resting state

. Furthermore, their activation alters lipid metabolism, influencing their function. Aerobic glycolysis and the pentose phosphate pathway are the main metabolic pathways for activated neutrophils.

Glycolysis regulates many essential functions of neutrophils, such as the respiratory burst and chemotaxis. Upon LPS or antigen stimulation, B lymphocytes exhibit enhanced glycolysis and mitochondrial metabolism, with glycolysis predominating. In contrast, regulatory T cells (Treg cells) and M2 macrophages primarily rely on oxidative phosphorylation fueled by fatty acid oxidation (FAO) for energy production. Different metabolic patterns also impact the differentiation of various immune cell subpopulations.

Therefore, exploring the mechanisms of metabolic reprogramming in immune cells and the influence of metabolism on immune cell function is essential not only for understanding the nature of immune responses but also their regulation.

Competition for Nutrients Between Tumor Cells and Immune Cells:

Metabolic reprogramming is not unique to cancer cells but is also a characteristic of other rapidly proliferating cells, such as activated T cells, Treg cells, neutrophils, and others. The tumor microenvironment (TME) is characterized by varying degrees and types of immune cell infiltration, similar to cancer cells; tumor-infiltrating lymphocytes (TILs) require nutrients from the TME for proliferation and differentiation. Studies indicate that tumors inhibit the function of tumor-infiltrating T cells by competitively consuming glucose.

The glycolytic activity of cancer cells may limit the glucose consumption of TIL T cells, inducing T cell exhaustion and immune escape. Indeed, the significant glucose uptake by tumors in the microenvironment is likely to inhibit T cell function by affecting T cell metabolic patterns.

Besides glucose, competition for amino acids, glutamine, fatty acids, and other metabolites or growth factors between tumor cells and immune cells, as well as the expression of corresponding transporters on cell surfaces, remains a significant factor influencing immune cell function (as depicted in Figure 2). Furthermore, the high levels of lactate, low pH, hypoxia, and elevated levels of reactive oxygen species (ROS) are also widespread in the TME, ultimately leading to cancer progression and immune evasion.

Therefore, targeting these metabolic pathways within tumors holds promise as a strategy to overcome the detrimental effects of metabolic competition between tumors and the immune system and enhance tumor immunogenicity.

Figure 2: Nutrient competition between tumor cells and immune cells within the tumor.

Metabolism-Based Drug Development:

Currently, there are several small molecule inhibitors that have been well-characterized and reported to target cancer metabolism, with both on-target and off-target effects, serving as a theoretical basis for clinical application.

For instance, inhibiting glucose uptake presents a therapeutic opportunity and has made progress in some studies (as shown in Figure 3).

STF-31 is a small molecule inhibitor of glucose transporter 1 (GLUT1), exhibiting characteristics of a glucose transporter inhibitor, and has shown efficacy in xenograft models of renal cell carcinoma in vivo.

However, this compound has off-target effects. Another GLUT inhibitor, Glutor, was identified by screening for 2-deoxyglucose uptake inhibitors.

Glutor targets GLUT1, GLUT2, and GLUT3 to inhibit glycolytic flux, with higher IC50 values due to overexpression of these glucose transporters.

BAY-876 was derived from a compound screen involving GLUT1+ DLD1 cells in colorectal adenocarcinoma and GLUT1− DLD1 cells, where ATP production was reduced.

Structure-activity relationship studies were used to develop BAY-876, which has a nanomolar IC50 against GLUT1 but is 100 times less active against GLUT2, GLUT3, and GLUT4.

While no in vivo studies of Glutor or BAY-876 have been provided in these studies, there have been reports that a related compound, BAY-897, impairs tumor growth in xenograft models derived from triple-negative breast cancer patients.

Whether these compounds possess the required pharmacokinetic properties for clinical translation remains to be determined.

Because cancer metabolism has emerged as a field of interest in the past two decades, many metabolic inhibitors have been mentioned or studied in the literature, but evidence of specificity or appropriate pharmacokinetic or pharmacodynamic markers is lacking.

Therefore, the development of specific inhibitors for enzymes or transporters, coupled with thorough medicinal chemistry, structural biology, and appropriate pharmacokinetic and pharmacodynamic studies, is crucial for clinical advancement.

Figure 3: Glucose metabolism inhibitors.

In Conclusion:

Targeting cancer and/or immune cell metabolism can synergize with anti-tumor immunity.

Understanding and harnessing metabolic crosstalk within tumor and immune cells holds the potential to improve the low response rates typically achieved with immunotherapy.

Although combinations of various metabolic drugs and immunotherapies have been applied in clinical trials, a better understanding of the metabolic mechanisms underlying tumor immune evasion and the metabolic requirements of immune cells is essential for fully exploiting the potential of combination therapies.

It’s noteworthy that not only does the metabolic programming of cancer cells affect antigen presentation and recognition by immune cells, but the metabolic programming of immune cells also influences their function, leading to changes in tumor immunogenicity.

Thus, metabolic interventions have the potential not only to enhance immune responses against highly immunogenic cancers but also to increase the immunogenicity of cancer cells, broadening the range of cancers that can benefit from immunotherapy.

Can Metabolic Interventions Enhance the Efficacy of Cancer Immunotherapy?

(source:internet, reference only)

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