Aspects of Cancer Cell Metabolism Related to Immunology

Hayak Tomiso^*
*Correspondence: Hayak Tomiso, Department of Pharmacy, University of Gadjah Mada, Yogyakarta, Indonesia, Email:

Introduction

Cancer, a complex and multifaceted disease, is characterized by the uncontrolled growth and spread of abnormal cells. A critical aspect of cancer biology is the unique metabolic reprogramming of cancer cells, which supports their rapid proliferation and survival. This metabolic reprogramming is closely intertwined with the immune system, as the metabolic activities of cancer cells can influence immune responses and vice versa. Understanding the interplay between cancer cell metabolism and immunology offers potential therapeutic avenues for enhancing anti-cancer immune responses and targeting cancer metabolism [1].

Cancer cells undergo significant metabolic changes to meet the demands of rapid proliferation and survival in often hostile environments. These changes, collectively known as metabolic reprogramming, include increased glucose uptake, enhanced glycolysis, and altered lipid and amino acid metabolism.

One of the hallmark features of cancer metabolism is the Warburg effect, named after Otto Warburg, who first described the phenomenon. Cancer cells preferentially convert glucose to lactate via glycolysis, even in the presence of sufficient oxygen for oxidative phosphorylation. This metabolic shift, known as aerobic glycolysis, provides several advantages to cancer cells, including rapid ATP production and the generation of metabolic intermediates necessary for biosynthesis.

Description

Cancer cells also exhibit alterations in lipid metabolism, which are essential for membrane synthesis, energy storage, and signaling. Increased fatty acid synthesis and uptake, along with enhanced lipid droplet formation, are commonly observed in cancer cells. These changes support the energetic and structural demands of proliferating tumor cells. Amino acid metabolism is another critical aspect of cancer cell metabolism. Glutamine, in particular, is a major nutrient for cancer cells, fueling the tricarboxylic acid cycle and providing nitrogen for nucleotide and amino acid biosynthesis. Alterations in the uptake and utilization of other amino acids, such as serine and glycine, also support cancer cell growth and survival.

The metabolic reprogramming of cancer cells not only supports their growth but also impacts the tumor microenvironment including immune cells. The metabolic interactions between cancer cells and immune cells can either promote or inhibit anti-tumor immune responses. Immune cells, like cancer cells, undergo metabolic reprogramming in response to their activation and the TME. For instance, activated T cells shift from OXPHOS to glycolysis to meet the energetic and biosynthetic demands of proliferation and effector function. Similarly, macrophages and other myeloid cells exhibit distinct metabolic profiles depending on their activation state (e.g., M1 macrophages are glycolytic, while M2 macrophages rely on OXPHOS and fatty acid oxidation) [2].

Cancer cells and immune cells compete for nutrients in the TME, which can influence immune responses. For example, the high glucose consumption by cancer cells can limit glucose availability for T cells, impairing their function. Similarly, cancer cells can deplete amino acids like glutamine and tryptophan, further suppressing immune cell activity. Cancer cells produce various metabolites that can suppress immune responses. Lactate, a byproduct of glycolysis, can inhibit T cell proliferation and cytokine production. Additionally, cancer cells often express enzymes like indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan into immunosuppressive kynurenine, contributing to T cell dysfunction. Metabolic checkpoints regulate immune cell function and can be targeted to enhance anti-tumor immunity. These checkpoints include key metabolic pathways and enzymes that control the balance between anabolic and catabolic processes in immune cells.

The mechanistic target of rapamycin is a central regulator of cell growth and metabolism, integrating signals from nutrients, growth factors, and energy status. In T cells, mTOR activation promotes glycolysis and effector function, while its inhibition supports memory T cell formation and longevity. Modulating mTOR activity can thus influence the balance between effector and memory T cells in the TME. AMP-activated protein kinase is a key energy sensor that promotes catabolic processes to restore energy balance under low nutrient conditions. In immune cells, AMPK activation supports metabolic adaptations that enhance survival and function in nutrient-poor environments. Targeting AMPK can improve the metabolic fitness of immune cells in the TME, enhancing their anti-tumor activity [3].

Immune checkpoint proteins like programmed death-1 and its ligand PD-L1 regulate T cell activity and exhaustion. PD-1 signaling inhibits glycolysis and promotes lipid oxidation in T cells, leading to reduced effector function. Blockade of the PD-1/PD-L1 axis can restore glycolytic metabolism and enhance T cell-mediated anti-tumor responses.Therapeutic strategies that target cancer metabolism can potentially enhance the efficacy of immunotherapies. By modulating the metabolic environment of the TME, these strategies aim to improve immune cell function and reduce tumor growth. Inhibiting glycolysis in cancer cells can reduce their growth and alter the TME to support immune cell function. Glycolysis inhibitors, such as 2-deoxyglucose and dichloroacetate have shown promise in preclinical studies. By reducing lactate production and increasing glucose availability, these inhibitors can enhance T cell activity and improve anti-tumor immunity. Cancer cells rely heavily on glutamine metabolism for growth and survival. Inhibitors of glutaminase, the enzyme that converts glutamine to glutamate, have shown anti-tumor effects in preclinical models. Targeting glutamine metabolism can also reduce the production of immunosuppressive metabolites, thereby enhancing immune responses.

Targeting lipid metabolism in cancer cells can disrupt their energy supply and biosynthetic processes. Inhibitors of fatty acid synthesis, such as orlistat and TVB-2640, have shown potential in reducing tumor growth. Additionally, modulating lipid metabolism can affect the function of myeloid cells in the TME, promoting a pro-inflammatory and anti-tumor phenotype. Combining metabolic inhibitors with immunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, offers a promising approach to enhance anti-tumor responses. By simultaneously targeting cancer metabolism and boosting immune function, combination therapies can overcome the limitations of single-agent treatments and improve clinical outcomes [3].

Combining metabolic inhibitors with immune checkpoint inhibitors, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, can enhance T cell function and reduce tumor immune evasion. For example, combining glycolysis inhibitors with PD-1 blockade has shown synergistic effects in preclinical models, leading to improved T cell infiltration and tumor regression. Adoptive cell therapies, such as chimeric antigen receptor (CAR) T cell therapy, can be enhanced by modulating the metabolic environment of the TME. Preconditioning the TME with metabolic inhibitors can improve the persistence and function of adoptively transferred T cells, leading to more effective tumor clearance. The interplay between cancer cell metabolism and immunology is a rapidly evolving field, with ongoing research uncovering new insights and therapeutic targets [4].

Developing metabolic biomarkers can help identify patients who are likely to benefit from metabolic-targeted therapies. Biomarkers related to glucose, lipid, and amino acid metabolism can guide personalized treatment strategies and monitor therapeutic responses. Comprehensive metabolic profiling of immune cells in the TME can provide insights into their functional states and vulnerabilities. Single-cell metabolic profiling techniques, such as mass spectrometry and imaging mass cytometry, can reveal metabolic heterogeneity and identify novel therapeutic targets. Integrating metabolic and immune therapies requires a deep understanding of the dynamic interactions between cancer cells and immune cells. Combination therapies should be designed based on the metabolic and immunological context of each patient's tumor, with the goal of maximizing therapeutic efficacy while minimizing toxicity [5]. The gut microbiome influences both cancer metabolism and immune responses. Modulating the microbiome through diet, probiotics, or fecal microbiota transplantation can impact the metabolic environment of the TME and enhance anti-tumor immunity. Understanding the complex interactions between the microbiome, cancer metabolism, and the immune system is an emerging area of research with significant therapeutic potential.

Conclusion

Cancer cell metabolism and immunology are intricately linked, with metabolic reprogramming in cancer cells influencing immune responses and vice versa. Understanding the metabolic interplay between cancer cells and immune cells provides new opportunities for therapeutic intervention. By targeting key metabolic pathways and enhancing immune cell function, we can develop more effective treatments that harness the power of the immune system to fight cancer. The future of cancer therapy lies in the integration of metabolic and immunological approaches, offering hope for improved outcomes for patients with cancer.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Zhang, Ji, Natalya N. Pavlova and Craig B. Thompson. "Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine." EMBO J 36 (2017): 1302-1315.

Google Scholar, Crossref, Indexed at

2. Liu, Yang, Tingli Zhao, Zhengzheng Li and Lai Wang, et al. "The role of ASCT2 in cancer: A review." Eur J Pharmacol 837 (2018): 81-87.

Google Scholar, Crossref, Indexed at

3. Wen, Yang-An, Xiaopeng Xing, Jennifer W. Harris and Yekaterina Y. Zaytseva, et al. "Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer." Cell Death Dis 8 (2017): e2593-e2593.

Google Scholar, Crossref, Indexed at

4. Yao, Cong-Hui, Ronald Fowle-Grider, Nathanial G. Mahieu and Gao-Yuan Liu, et al. "Exogenous fatty acids are the preferred source of membrane lipids in proliferating fibroblasts." Cell Chem Biol 23 (2016): 483-493.

Google Scholar, Crossref, Indexed at

5. Mashima, T., H. Seimiya and T. J. B. J. O. C. Tsuruo. "De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy." Brit J Cancer 100 (2009): 1369-1372.

Google Scholar, Crossref, Indexed at