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The Metabolic Regulation of the NKG2D-Positive NK and T Cells and Their Role in Disease Progression

Jiayi Tang¹, Yaqi Lu¹, Min Chen¹

¹Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.

|November 27, 2025

Abstract:

Natural killer (NK) cells are the main cytotoxic lymphocytes of the natural immune system, which play an important role in tumor immune surveillance and anti-viral response. The surface receptor NKG2D can recognize NKG2D ligands on the surface of tumor or metabolism-stressed cells, thereby activating immune responses and mediating cytotoxicity and anti-tumor activity of NK cells. However, NKG2D-positive NK cells are regulated by metabolites, and play a negative role in metabolic diseases. Various metabolites, including lipids, reactive oxygen species (ROS), glucose and amino acids, regulate NKG2D expression and NK cell activity and decide the immune microenvironment of pathological tissue. Thus, targeted therapies based on NKG2D-positive NK cell have entirely different strategies in the treatment of tumor or metabolic diseases. This article focuses on the metabolic regulation of NKG2D-positive NK cells and their opposite roles in disease progression, including of cancer and metabolic disease. In the future, in-depth studies of the regulatory mechanisms of the NKG2D signaling pathway by metabolites and the optimization of the safety and efficacy of targeted therapeutic strategies will lead to new breakthroughs in the treatment of tumors and metabolic diseases, providing patients with more effective treatment options.

Insights

Metabolites regulate natural killer (NK) cells via the NKG2D receptor, impacting cancer and metabolic diseases differently. Understanding these mechanisms is key for developing targeted therapies.

Area of Science:

Immunology
Metabolism
Cell Biology

Background:

Natural killer (NK) cells are crucial cytotoxic lymphocytes in innate immunity, vital for tumor surveillance and antiviral responses.
The NKG2D receptor on NK cells recognizes ligands on stressed cells, activating cytotoxicity and anti-tumor functions.
Metabolites influence NKG2D expression and NK cell activity, playing dual roles in cancer and metabolic diseases.

Purpose of the Study:

To explore the metabolic regulation of NKG2D-positive NK cells.
To elucidate the opposing roles of NKG2D-positive NK cells in cancer versus metabolic diseases.
To highlight the potential for targeted therapies based on NKG2D-positive NK cell modulation.

Main Methods:

Review of existing literature on NK cell metabolism and NKG2D signaling.
Analysis of how various metabolites (lipids, ROS, glucose, amino acids) affect NKG2D expression and NK cell function.
Comparative analysis of NKG2D-positive NK cell roles in tumor immunity and metabolic pathology.

Main Results:

Metabolites differentially regulate NKG2D expression and NK cell activity.
NKG2D-positive NK cells exhibit distinct functions in tumor immunity (beneficial) and metabolic diseases (detrimental).
Metabolic regulation of NK cells significantly shapes the immune microenvironment in pathological tissues.

Conclusions:

Targeted therapeutic strategies for NKG2D-positive NK cells must be tailored to specific diseases like cancer or metabolic disorders.
Further research into metabolite-NKG2D pathway interactions is essential for optimizing therapeutic efficacy and safety.
Understanding these complex regulatory mechanisms promises novel treatment options for cancer and metabolic diseases.

Read full analysis

Keywords:

NKG2D cell therapy metabolic disease metabolic regulation natural killer cells

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