A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle

Abstract

Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.

Keywords: Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment.

Fig. 1

Glutamine emerges as a rising star in the field of cancer immunotherapy. A The timeline of major breakthroughs in glutamine metabolism. B The dynamic interplay between cancer cells and immune cells in their competition for the limited pool of available glutamine. GLS, glutaminase

Fig. 2

Glutamine addiction in cancer cells. A The process of glutamine catabolism in tumor cells, as well as potential gene alterations that can impact glutamine metabolism. Glutamine is transported into the cell through membrane amino acid transporters, such as SLC1A5, SLC6A14, and SLC38A1/2, where it undergoes a dehydrogenation reaction catalyzed by GLS to form glutamate. Glutamate then converts to α-KG through the action of GLUD, GOT or GPT, entering the TCA cycle for energy production. The green region represents the influence of various gene alterations on different nodes of glutamine metabolism. B Multiple glutamine transporter proteins have been observed to undergo upregulation across different types of cancer. GLS, glutaminase; GPT, glutamate pyruvate transaminase; GOT, glutamic-oxaloacetic transaminase; GLUD, glutamate dehydrogenase; α-KG: α-ketoglutarate; TCA: tricarboxylic acid; TNBC: triple-negative breast cancer; NSCLC: non-small cell lung cancer; HNSCC: head and neck squamous cell carcinoma; ER + : estrogen receptor positive

Fig. 3

The impact of glutamine metabolism inhibition on diverse immune cell populations. Created with BioRender.com. TANs, tumor-associated neutrophils; TAMs, tumor-associated macrophages; NK, natural killer; MDSCs: myeloid-derived suppressive cells; IFN, interferons; IL, interleukin; TNF: tumor necrosis factor

Fig. 4

Tumor-induced glutamine metabolic competition shapes immune cell responses in the tumor microenvironment. A Tumor-induced glutamine competition leads to reduced uptake in immune cells. B Tumor-induced glutamine competition via mTOR pathway to regulate immune function. C Tumor-induced glutamine competition via the PD-1/PD-L1 axis to regulate immune function. D Tumor-induced glutamine competition promotes glutamate secretion to modulate immune responses. Red solid T arrows direct inhibitory interactions. Created with BioRender.com. TANs, tumor-associated neutrophils; TAMs, tumor-associated macrophages; NK, natural killer; Tregs, regulatory T cells; MDSCs, myeloid-derived suppressive cells; PD-1, programmed cell death 1; PD-L1, programmed cell death-ligand 1; IFN, interferons; IL, interleukin; TME, tumor microenvironment

Fig. 5

The impact of targeting glutamine metabolism on the tumor immune microenvironment via three distinct avenues: glutamine antimetabolites, inhibitors of glutamine catabolic-related enzymes, and blockers of glutamine uptake. Red solid T arrows direct inhibitory interactions. Created with BioRender.com. GLS, glutaminase; GPT, glutamate pyruvate transaminase; GOT, glutamic-oxaloacetic transaminase; GLUD, glutamate dehydrogenase; CTLs, cytotoxic T lymphocytes; TCA, tricarboxylic acid; TME, tumor microenvironment; AOA: amino-oxyacetic acid