Enhancing Natural Killer Cell Efficiency through Glycolysis Restriction: A Novel Approach to Serial Killing

Marconi Suvadi^*
*Correspondence: Marconi Suvadi, Department of Immunology, University of Catania, 95123 Catania, Italy, Email:

Introduction

Enhancing Natural Killer (NK) cell efficiency through glycolysis restriction represents a ground-breaking paradigm shift in immunotherapy, offering a novel approach to bolstering the innate immune response against cancer and viral infections. Natural Killer cells, a subset of cytotoxic lymphocytes, play a pivotal role in immune surveillance, identifying and eliminating aberrant cells without the need for prior sensitization, thus serving as the body's first line of defense against malignant transformation and viral invasion. Central to their function is their ability to execute "serial killing," whereby a single NK cell can eliminate multiple target cells successively, enhancing their cytotoxic potency [1]. This phenomenon is tightly regulated by metabolic processes, particularly glycolysis and the primary energy-generating pathway in NK cells. Glycolysis, while essential for NK cell activation and effector functions, can also impose limitations on their longevity and serial killing capacity. The reliance on glycolysis for energy production leads to rapid depletion of metabolic intermediates, impairing NK cell persistence and functionality within the tumor microenvironment or during prolonged viral infections. Hence, modulating glycolytic metabolism emerges as a promising strategy to enhance NK cellmediated immunity [2].

Description

Recent studies have demonstrated that restricting glycolysis can potentiate NK cell effector functions and prolong their survival, thereby augmenting their ability to execute serial killing. By targeting key enzymes and transporters involved in glycolysis, such as hexokinase and glucose transporters, researchers have successfully manipulated NK cell metabolism to favor oxidative phosphorylation, a more sustainable energy-generating pathway. This metabolic reprogramming not only enhances NK cell longevity but also preserves their cytotoxic potential, enabling them to sustain prolonged attacks against tumor cells or virally infected targets. One approach to glycolysis restriction involves pharmacological interventions targeting glycolytic enzymes or metabolic checkpoints. Small molecule inhibitors, such as 2-Deoxyglucose (2-DG) and lonidamine, have been shown to suppress glycolysis in NK cells, resulting in enhanced anti-tumor activity in preclinical models. These inhibitors disrupt glucose uptake or glycolytic flux, forcing NK cells to rely more on mitochondrial respiration for energy production. Consequently, NK cells exhibit increased persistence and cytotoxicity, leading to improved tumor control and immune surveillance. Furthermore, genetic manipulation of metabolic regulators offers another avenue to modulate NK cell metabolism and enhance their effector functions. By overexpressing or silencing key metabolic genes, researchers can fine-tune the balance between glycolysis and oxidative phosphorylation in NK cells, thereby optimizing their anti-tumor or anti-viral responses. For instance, knockout of the glycolytic enzyme Phosphofructokinase-2/Fructose-2,6-Bisphosphatase 3 (PFKFB3) in NK cells has been shown to dampen glycolysis while promoting mitochondrial respiration, resulting in potentiated cytotoxicity and prolonged survival in tumor-bearing mice [3].

Natural Killer (NK) cells, a critical component of the innate immune system, play a pivotal role in host defense against infected or malignant cells. Their ability to recognize and eliminate abnormal cells without prior sensitization makes them a promising target for immunotherapy against various diseases, including cancer. Recent studies have shed light on the metabolic regulation of NK cell function, highlighting the significance of glycolysis in dictating their effector responses. Interestingly, restricting glycolysis has emerged as a novel strategy to enhance NK cell cytotoxicity and augment their serial killing capacity. Glycolysis, the metabolic pathway responsible for the conversion of glucose into pyruvate, serves as a major energy source for immune cells, including NK cells. Upon activation, NK cells rapidly up regulate glycolysis to meet their increased energy demands and support effector functions such as cytokine production and cytotoxicity. However, sustained glycolytic activity can lead to metabolic exhaustion and impair NK cell functionality, ultimately compromising their ability to eradicate target cells efficiently [4].

Intriguingly, recent studies have demonstrated that limiting glycolysis through various mechanisms can potentiate NK cell cytotoxicity and improve their anti-tumor activity. One such approach involves targeting key enzymes involved in glycolysis, such as hexokinase or 6-Phosphofructo-2-Kinase/ Fructose-2,6-Biphosphatase 3 (PFKFB3), which regulate different steps of the glycolytic pathway. By inhibiting these enzymes, researchers have observed a shift in NK cell metabolism towards alternative energy pathways, such as oxidative phosphorylation, leading to enhanced effector functions and prolonged survival. Importantly, glycolysis restriction not only augments NK cell-mediated cytotoxicity but also enhances their immunomodulatory functions, including cytokine production and immune memory formation. By favoring oxidative metabolism, NK cells exhibit heightened cytokine secretion, such as Interferon-Gamma (IFN-γ) and Tumor Necrosis Factor-Alpha (TNF-α), which play crucial roles in orchestrating anti-tumor immune responses and shaping adaptive immunity. Moreover, metabolic reprogramming can imprint longlasting changes in NK cell phenotype and function, enabling the generation of memory-like NK cells capable of mounting rapid and robust immune responses upon re-encounter with cognate antigens [5].

The therapeutic potential of enhancing NK cell efficiency through glycolysis restriction extends beyond cancer immunotherapy to encompass viral infections, where NK cells serve as key players in the early defense against viral pathogens. By bolstering NK cell-mediated viral clearance, glycolysis restriction offers a promising strategy to combat emerging viral threats, including influenza, HIV and SARS-CoV-2. Preclinical studies have shown that manipulating NK cell metabolism can enhance their ability to control viral replication and reduce viral load, highlighting the translational relevance of metabolic immunotherapy in combating infectious diseases. Furthermore, recent advances in genetic engineering have enabled the development of Chimeric Antigen Receptor (CAR) NK cells with enhanced cytotoxicity and specificity against tumor cells. By incorporating glycolysis-targeting strategies into CAR NK cell design, researchers have demonstrated improved tumor killing and prolonged persistence in preclinical models, paving the way for the clinical translation of these engineered cells as a promising immunotherapy option [3,5].

Conclusion

In conclusion, enhancing NK cell efficiency through glycolysis restriction represents a transformative approach to immunotherapy, offering new avenues for the treatment of cancer and viral infections. By modulating NK cell metabolism, researchers can potentiate their cytotoxicity, prolong their survival and augment their immunomodulatory functions, thereby enhancing their ability to eradicate malignant cells or combat viral pathogens. Future studies aimed at elucidating the precise mechanisms underlying metabolic reprogramming in NK cells and optimizing therapeutic interventions hold immense promise for advancing the field of immunometabolism and translating these findings into clinical applications. By restricting glycolysis, either through pharmacological inhibition, metabolic reprogramming, or genetic engineering, researchers can potentiate NK cell cytotoxicity and improve their serial killing capacity against tumor cells. Future studies aimed at elucidating the underlying mechanisms and optimizing therapeutic strategies hold promise for the development of novel immunotherapies that harness the metabolic vulnerabilities of NK cells to combat cancer and other diseases.

Acknowledgment

None.

Conflict of Interest

There are no conflicts of interest by author.

References

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