Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Introduction

Nitrogen is one of the core elements of life activities and is involved in the composition of biological macromolecules such as proteins and nucleic acids. Nitrogen metabolism has a key role in maintaining normal physiological functions of the organism, including protein synthesis, nucleotide synthesis and ammonia detoxification. Proteins are the main performers of life activities, and their synthesis requires sufficient nitrogen sources to construct amino acid residues. The synthesis of nucleotides, the basic building blocks of nucleic acids, is likewise dependent on the raw materials provided by nitrogen metabolism. In addition, ammonia detoxification is an important aspect of nitrogen metabolism, as the liver prevents ammonia toxicity by converting ammonia to urea through the urea cycle.

Tumor cells undergo metabolic reprogramming to adapt to rapid proliferation and harsh microenvironment. Nitrogen metabolism reprogramming is one of the key aspects, in which tumor cells satisfy their large demand for nitrogen sources by enhancing glutamine uptake and metabolism, and altering nitrogen metabolism enzyme expression. This reprogramming not only supports the rapid growth of tumor cells, but also helps them to survive under unfavorable conditions such as nutrient deprivation and hypoxia.

The aim of this paper is to deeply explore the relationship between nitrogen metabolism and tumor. Firstly, it introduces the characteristics of nitrogen metabolism in normal human body, which lays the foundation for understanding the changes of nitrogen metabolism in tumors. Then focusing on the reprogramming of nitrogen metabolism in tumor patients, analyzing its characteristics and effects on tumor growth. Then, we describe the regulation of nitrogen metabolism by key enzymes in the tumor microenvironment, and reveal the mechanism of their influence. Finally, the regulatory mechanism of nitrogen metabolism in tumors is discussed, and analyzed from the levels of transcription factors, signaling pathways, epigenetic and so on. Through systematic elaboration, the key role of nitrogen metabolism in tumor development will be elucidated, which will provide a theoretical basis for the development of new tumor therapeutic strategies.

Nitrogen metabolism

Nitrogen-related metabolism in normal body

Nitrogen is one of the indispensable elements in the living body, mainly involved in the synthesis and metabolism of proteins, nucleic acids (DNA and RNA), amino acids, nucleotides and other important biological molecules. The human body obtains nitrogen through the intake of nitrogenous compounds (e.g. proteins) and maintains nitrogen balance through a series of complex metabolic pathways.

Amino acid metabolism

Amino acid utilization

Amino acids are the core molecules of nitrogen metabolism and are used in the synthesis of proteins, nucleotides, neurotransmitters (e.g., glutamate, GABA), and other nitrogen-containing compounds. They include both essential and nonessential amino acids. Essential amino acids (e.g., leucine, isoleucine, valine) need to be ingested from the diet, while nonessential amino acids (e.g., glutamine, aspartic acid, alanine) can be synthesized by the cells themselves. Amino acids are involved in metabolism through transamination, deamination, and decarboxylation. Transaminases (e.g., ALT, AST) catalyze the amino transfer between amino acids and α-keto acids to produce new amino acids and keto acids. Amino acids are released from amino acids (NH₃) by oxidative deamination or combined deamination to produce the corresponding α-keto acids.

Ammonia metabolism and detoxification

Because of its low solubility in water and toxicity, ammonia needs to be bound to a carrier molecule before it can be transported in the bloodstream. Ammonia is detoxified by two main pathways, one of which is the urea cycle: most of the ammonia is converted to urea in the liver via the urea cycle. The urea cycle involves several enzymatic reactions that ultimately convert ammonia and carbon dioxide to urea. Urea is a non-toxic substance that can be excreted from the body through urine. The second is glutamine synthesis: some of the ammonia combines with glutamic acid to form glutamine. This process is catalyzed by glutamine synthetase. Glutamine can enter the bloodstream and be transported to the kidneys and other tissues, where it releases ammonia for further participation in the urea cycle or for excretion through the urine. Small amounts of ammonia can also be excreted through sweat.

Nucleotide metabolism

Nitrogen is an important component of nucleotides (purines and pyrimidines). Glycine, glutamine, and aspartic acid provide nitrogen atoms for purine synthesis. Pyrimidine synthesis is provided with nitrogen atoms by glutamine and aspartic acid. Purine catabolism eventually produces uric acid (a nitrogenous waste product), while pyrimidine catabolism produces beta-alanine or beta-aminoisobutyric acid.

Characteristics of nitrogen metabolism in cancer patients

Nitrogen metabolism reprogramming

Energy metabolic reprogramming, i.e., promoting rapid cell growth and proliferation by adjusting energy metabolism, is considered an emerging hallmark of cancer(Hanahan and Weinberg 2011 ). In order to meet their needs for rapid proliferation or survival, cancer cells enhance nitrogen uptake and metabolism and have an increased demand for amino acids to support rapid proliferation, processes that are usually accompanied by ammonia production.

Metabolic reprogramming of key amino acids

Glutamine metabolism (non-essential amino acids)

Glutamine is one of the major amino acids biosynthesized during cell growth and division. The carbon in glutamine is used in the synthesis of fatty acids and amino acids, and the nitrogen is involved in the production of purines and pyrimidines. Major sources of glutamine include lung, liver, brain, adipose tissue, and skeletal muscle because of their high tissue-specific glutamine synthesis activity, which catalyzes the synthesis of glutamine from glutamate and ammonia in cells and tissues that synthesize glutamine(Nan et al. 2025 ).

Glutamine metabolism sustains tumor survival and progression, being involved in multiple anabolic processes including nucleotide synthesis, amino acid production, protein glycosylation modification, extracellular matrix production, epigenetic modification, maintenance of cellular redox balance and autophagy(Fan et al. 2020 ). It was found that glutamine can be involved in the metabolism of cancer stem cells (CSC)(Pacifico et al. 2023 ). Most cancers, including melanoma, breast cancer and pancreatic ductal adenocarcinoma have a high glutamine requirement(Li et al. 2023a ; Ratnikov et al. 2017 ; Recouvreux et al. 2024 ). Although upregulation of glutamine metabolism is a phenomenon present in many cancer cells, recent studies have demonstrated reduced glutamine metabolism in cholangiocarcinoma, glioblastoma multiforme, hepatocellular carcinoma, and thyroid carcinoma, demonstrating tissue heterogeneity in glutamine metabolism(Xue et al. 2024 ). Even tumors occurring in the same organ may exhibit different glutamine metabolism patterns among different cancer subtypes. Luminal breast cancer usually shows high glutamate-ammonia ligase (GLUL) and low glutaminases (GLS) expression, while basal breast cancer is the opposite(Kung et al. 2011 ). These observations indicate that oncogenic rewiring alone cannot fully account for glutamine dependence; instead, glutamine metabolism is shaped by the combined influence of tumor-intrinsic genetic programs, tissue metabolic architecture, and microenvironmental nutrient pressures.

For the heterogeneity of glutamine metabolism among tumors, the first factor to consider is biological factors. Within different tumors, oncogenic signaling pathways and gene mutations directly drive the reprogramming of metabolic programs. tP53 is mutated or absent in most tumors. On the one hand, p53 promotes glutamine metabolism in tumor cells and promotes cancer cell survival by up-regulating GLS2 to make them tolerant to glutamine deficiency. However, on the other hand, p53 also increases glutathione (GSH) levels in tumor cells, decreases ROS, and inhibits tumorigenesis(Suzuki et al. 2010 ; Tran et al. 2017 ).

K-Ras is known to sensitize tumor cells to glutamine deficiency, inhibit lactate dehydrogenase A (LDHA) expression, and increase aspartate aminotransferase expression. In KRAS mutant tumors (such as pancreatic ductal adenocarcinoma and colorectal cancer), KRAS mutation leads to the upregulation of the expression of SLC7A5, SLC38A2 and SLC25A22 transporters in cancer cells(Wu et al. 2024 ), when Ras is activated, glutamine is the main carbon source for the TCA cycle(Dilshara et al. 2017 ; Son et al. 2013 ). HIF-1α and HIF-2α are highly expressed in most tumors(Talks et al. 2000 ), In the human non-small cell lung cancer cell line A549, silencing of HIF-1α expression was found to reduce glutamine depletion in tumor cells(Faubert et al. 2014 ). In addition, HIF-2α has been reported to enhance the activity of c-MYC, which in turn drives glutamine catabolism by regulating many genes, including glutaminases(Gao et al. 2009 ).

In MYC-driven tumors (such as Burkitt’s lymphoma and some small cell lung cancers), metabolism is dependent on glutamine. MYC directly transcriptionally upregulates glutamine transporters (SLC1A5, SLC7A5) and GLS, further providing energy for the tricarboxylic acid cycle and biosynthesis processes(Ganguly et al. 2022 ; Gouw et al. 2019 ; Zhao et al. 2019 ). These gene-level differences are closely coupled with the tissue origin and differentiation status of tumor cells. In addition, environmental factors in the tumor microenvironment, such as hypoxia-induced hypoxia-inducible factor HIF-1α, drive the conversion of glutamine to lipid precursors. This pathway is particularly significant in constitutive HIF-activated tumors such as renal cell carcinoma, which are caused by VHL deficiency (Zhao et al. 2025 ). The cellular metabolic competition in the tumor microenvironment, such as the intense competition between cancer cells and immune cells (especially activated T cells and macrophages with specific functions) for the limited glutamine, forces adaptive evolution in the cell population and drives the formation of glutamine metabolic heterogeneity. For instance, glutamine deficiency can inhibit the mTORC1 signaling pathway of T cells, affecting their differentiation and anti-tumor functions (Feng et al. 2024 ). Tumor cells adapt to this pressure through multiple reprogramming strategies, not only by upregulating glutamine transporters to enhance uptake capacity, but also by demonstrating complex cellular cooperative behavior. The latest research has found that when there is a lack of nutrition, high-density tumor cell populations will secrete extracellular aminopeptidase CNDP2 to break down oligopeptides, establishing a shared glutamine “public resource pool”, which enables the formation of dominant clones in sparse vascular areas, while non-cooperative cells are eliminated. More importantly, this metabolism-immune interaction is dynamic and bidirectional(Guzelsoy et al. 2025 ). The metabolic adaptation of tumor cells, in turn, reshapes the immune microenvironment and determines the ultimate efficacy of immunotherapy. In triple-negative breast cancer, the excessive consumption of glutamine by some tumor cells through the HEBP2/GSTP1 axis can induce ferroptosis in CCL3 + macrophages with anti-tumor potential, thereby impairs the immune response(Xiao et al. 2025 ). These bidirectional effects not only influence the metabolic heterogeneity map of tumors but are also the key factors affecting the therapeutic efficacy.

Various targeted drugs are currently available that act on different properties of p53. For p53 wild-type tumours, the core strategy involves restoring or enhancing p53’s metabolic regulatory function. MDM2 (murine double minute 2) is a key E3 ubiquitin ligase whose primary function is to promote p53 protein degradation via ubiquitination, directing it towards the proteasome pathway for metabolism. A novel, highly potent MDM2 inhibitor, MI-1061, has been demonstrated to significantly activate wild-type p53 and effectively suppress the growth of cancer cells harbouring wild-type p53. Furthermore, in vivo studies reveal its marked ability to inhibit tumour progression(Acharyya et al. 2025 ). For p53-mutant tumours, the strategy shifts towards exploiting their specific metabolic addiction. Many refractory cancers (such as small cell lung cancer) exhibit abnormally hyperactive nitrogen metabolism processes. Multiple clinical trials targeting relevant nitrogen metabolism enzymes are currently underway (Table 2 ). Regarding downstream pathways, recent research reveals that 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog that inhibits glutamine metabolism by competitively inhibiting multiple glutamine-dependent enzymes, including the Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase (CAD), a vital rate-limiting metabolic enzyme in pyrimidine biosynthesis. CAD is the key enzyme that catalyzes the deamidation modification of p53 protein, thereby inactivating it, offering a novel approach for cancer treatment(Qi et al. 2025 ). The development of drugs that effectively target tumor nitrogen metabolism has entered an era of precision and combination therapy. Future drug development may deeply integrate upstream p53 pathway regulation, downstream metabolic enzyme-specific inhibition, and combination therapies based on synthetic lethality principles to achieve precise strikes against tumor metabolic vulnerabilities.

GLS in mitochondria of cancer cells catalyzes the conversion of glutamine to glutamate(Tabe et al. 2019 ), Ammonia is released when glutamate is further converted to α-KG by mitochondrial GLUD1. When α-KG enters the TCA cycle, it is oxidized to produce succinate and fumarate, which are cancer metabolites that produce ATP, NADH, and FADH2(Jin et al. 2023 ). Glutamine also produces α-KG through a redox process, which is a precursor for purine, pyrimidine and aspartate biosynthesis in tumor cells(Zhu et al. 2022 ). In addition, glutamine was found to enhance glucose oxidation and counteract α-KG depletion through essential amino acid (EAA) degradation(Quek et al. 2022 ). Recently, N-acetyl-aspartyl-glutamate (NAAG) has been identified as a reservoir of glutamate in cancer. In cancer cells, there is a significant increase in glutamine-producing NAAG, and high levels of NAAG are observed in advanced cancers(Nguyen et al. 2019 ). The NAAG storage cycle provides cancer cells with a mechanism for storing this important metabolite by converting glutamine-producing glutamate to NAAG and then back to glutamate(Zhang et al. 2022b ). In addition, glutamine metabolism promotes immune escape by affecting immune cell function in the tumor microenvironment. For example, high glutamine consumption by tumor cells leads to decreased levels of glutamine in the microenvironment, which inhibits the function of T cells and natural killer cells (NK cells), thus weakening the anti-tumor immune response(Leone et al. 2019 ). Cancer cell invasion is also influenced by glutamine metabolism. In colorectal cancer, the amount of GLS1 mRNA expressed is associated with lymph node metastasis(Bergers and Fendt 2021 ). Studies have shown that metastatic tumor cells support their survival in the circulation and colonization of distant organs through enhanced glutamine uptake and metabolism(Commisso et al. 2013 ).

Glutaminase inhibitors are used in clinical trials for antitumor therapy; however, some tumor cells are able to maintain survival under glutamine deprivation conditions through metabolic reprogramming (e.g., enhanced glucose metabolism or fatty acid oxidation). Therefore, combined targeting of glutamine metabolism and other metabolic pathways (e.g., glycolysis or mitochondrial function) may provide a more effective therapeutic strategy.

Asparagine is closely related to glutamine, mechanistically, glutamic acid and oxaloacetic acid are catalyzed by GOT2 to produce aspartic acid and α-KG, which then generates asparagine in the presence of asparagine synthetase. Notably, when glutamine is depleted, asparagine upregulates glutamine synthetase and increases glutamine levels again(Wang et al. 2024a ). Therefore, inhibition of asparagine synthesis is also an important target.

Aspartic acid (non-essential amino acid)

Aspartate is involved in the regulation of nitrogen homeostasis through the urea cycle and amino acid metabolism, as well as serving as an intermediate metabolite in the TCA cycle, providing cells with biosynthetic precursors (e.g., pyrimidine nucleotides) and supporting oxidative phosphorylation energy metabolism. However, tumor cells enhance aspartate synthesis and uptake in response to proliferative stress and microenvironmental nutrient limitation through metabolic reprogramming, upregulation of asparagine synthetase (ASNS) or dependence on the mitochondrial aspartate transporter (SLC1A3), among other pathways(Deng et al. 2020 ; Zhang et al. 2022 c). p53-deficient tumor cells promote cell survival and inhibit apoptosis through ASNS-mediated asparagine-aspartate homeostasis imbalance and activation of the LKB1-AMPK signaling pathway(Deng et al. 2020 ). This metabolic adaptation not only supports the biomolecule synthesis needs of tumor cells, but also maintains their stemness characteristics by regulating epigenetic modifications such as histone methylation(Zhang et al. 2022 c).

Abnormal remodeling of aspartate metabolism further affects tumor invasion and metastasis. Recent studies revealed that aspartate concentration in the lung metastatic microenvironment is significantly elevated, which promotes the formation of metastatic foci and angiogenesis by activating the NMDA receptor on the surface of cancer cells and triggering the downstream eIF5A-dependent collagen synthesis program(Doglioni et al. 2025 ). In addition, aspartic acid can also inhibit the AMPK pathway in adipose tissue and weaken the mitochondrial thermogenesis, thus remodeling the whole-body energy metabolic network and creating a favorable metabolic ecological niche for tumor growth(Dong et al. 2024 ).

Therapeutic strategies targeting aspartate metabolism are emerging as a new direction for precision tumor intervention. Preclinical studies have shown that inhibition of ASNS activity or the use of asparaginase (ASNase) effectively depletes the aspartate pool and induces apoptosis in p53-deficient tumor cells(Deng et al. 2020 ). Meanwhile, inhibitors targeting the aspartate transporter or NMDA receptor significantly inhibited the invasive capacity of a lung cancer metastasis model(Doglioni et al. 2025 ). In the field of nanomedicine design, researchers have demonstrated the potential of multimodal therapy by loaded biomimetic nanoparticles (e.g., ZIF(Fe)&CB NPs) with iron ions and metabolic inhibitors, which synergistically enhance intracellular reactive oxygen species (ROS) accumulation in tumor cells and block aspartate metabolism compensation pathway(Zhang et al. 2022 c).

Arginine (conditionally essential amino acid)

Under normal physiological conditions, arginine participates in the removal of nitrogen waste through the urea cycle, regulates vascular tone as a precursor of nitric oxide (NO), and supports cell proliferation and tissue repair in polyamine synthesis. However, malignant tumors subvert arginine metabolic homeostasis through metabolic reprogramming: for example, hepatocellular carcinoma (HCC), which lacks the ability to synthesize arginine on its own, significantly enhances the uptake efficiency by up-regulating arginine transport proteins (e.g., SLC6A14 and CAT-1) and inhibits the conversion of arginine to polyamines, resulting in the accumulation of high concentrations of arginine in the tumor microenvironment(Mossmann et al. 2023 ). This metabolic hijacking phenomenon is conserved in a variety of solid tumors, such as pancreatic cancer, which synthesizes polyamines by activating the ornithine aminotransferase (OAT) pathway in the presence of microenvironmental arginine deprivation, using glutamine to substitute for arginine in order to maintain tumor growth requirements(Lee et al. 2023 ).

Aberrant metabolism of arginine drives malignant tumor progression through multidimensional mechanisms. First, arginine remodels metabolic gene expression profiles through interactions with the RNA-binding protein RBM39, inducing the transformation of tumor cells to a dedifferentiated embryo-like state(Mossmann et al. 2023 ). Second, competitive depletion of arginine suppresses T cell immunoreactivity, e.g., glioblastoma depletes arginine from the microenvironment through upregulation of arginase (ARG1), leading to inactivation of CD8 + T cell function and promoting immune escape(Martí and Reith 2021 ). In breast cancer cells, spermine secreted by cancer cells is taken up by macrophages and converted to polyamines via the corresponding polyamine synthase, in which significantly elevated spermine can induce a shift in macrophages toward immunosuppression expressing M2-type markers, resulting in suppression of CD8 + T cell function(Zhu et al. 2025 ). In addition, arginine metabolite polyamines can activate pro-oncogenic signaling pathways (e.g., MAPK/ERK) and enhance the invasiveness and distal metastatic potential of tumor cells. Clinical cohort studies have shown that serum arginine levels in patients with hepatocellular carcinoma are significantly and positively correlated with the risk of tumor load and metastasis(Mossmann et al. 2023 ).

Therapeutic strategies targeting arginine metabolism are evolving from “total deprivation” to “precision intervention”. Studies focusing on targeting tumor-specific metabolic nodes, such as the use of Indisulam to selectively degrade RBM39 to block arginine-driven metabolic reprogramming, have demonstrated dose-dependent tumor suppressive effects in organoid models of hepatocellular carcinoma(Mossmann et al. 2023 ). Targeting OAT-dependent synthetic lethal strategies for pancreatic cancer or targeting tumor-specific pathways with metabolic inhibitors (e.g., 5-FMO) delivered via nanocarriers (Lee et al. 2023 ).

Branched chain amino acids (essential amino acids: leucine, isoleucine, valine)

Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are metabolized under normal physiological conditions mainly through the liver and muscle tissues, and are involved in protein synthesis, energy supply, and the regulation of signaling pathways. In healthy individuals, the metabolism of BCAAs is tightly regulated, and their catabolism is mainly accomplished through branched-chain amino acid aminotransferase (BCAT) and branched-chain α-ketoacid dehydrogenase complex (BCKDH), which ultimately enters the tricarboxylic acid cycle to provide energy for cells.

In cancer patients, the metabolism of BCAAs shows significant heterogeneity. It was found that the uptake and catabolism of BCAAs were significantly enhanced in a variety of tumor types (e.g., breast, lung, and colorectal cancers), which may be related to the high demand for energy and biosynthetic precursors in tumor cells(Ananieva 2015 ). Leucine promotes tumor cell proliferation and survival by activating the mammalian target of rapamycin (mTOR) signaling pathway(Mossmann et al. 2018 ). In addition, metabolic competition in the tumor microenvironment leads to redistribution of BCAAs, which are preferentially utilized by tumor cells for their rapid growth by upregulating the expression of key enzymes such as BCAT1 and BCKDH(Li et al. 2024 ). This metabolic reprogramming not only supports the bioenergetic requirements of tumor cells, but may also affect tumor invasion and metastatic capacity through epigenetic modifications and metabolite-mediated signaling.

BCAT is a metabolic enzyme associated with branched-chain amino acids (BCAAs), and is regarded as a prognostic biomarker for cancer. Overexpression of BCAT1 enhances the catabolism of BCAAs, supplying tumour cells with energy and biosynthetic precursors, thereby promoting tumour cell growth and proliferation. In triple-negative breast cancer and glioblastoma multiforme (GBM), BCAT1 plays a significant role in tumour migration, invasion, and proliferation(Li et al. 2023 c; Zhang et al. 2022a ). In gastric cancer (GC) research, the glutamate-induced alanine mutation at codon 61 (BCAT1E61A) within BCAT1 results in enhanced functionality. The elevated enzymatic activity of BCAT1E61A promotes the catabolic metabolism of branched-chain amino acids (BCAAs), accelerating cellular growth and metastasis. Furthermore, BCAT1 activates the PI3K/AKT/mTOR pathway, thereby facilitating tumour progression(Shu et al. 2021 ). BCAT1 is primarily localised in the cytoplasm. In contrast, BCAT2 functions predominantly within mitochondria, and extensive research indicates that BCAT2 plays a significant role in pancreatic ductal adenocarcinoma (PDACLee et al. 2019; Li et al. 2022b ). In melanoma (MM), BCAT2 has been identified as an oncogene that promotes melanoma progression(Tian et al. 2023 ). c(Kitagawa et al. 2023 ). BCKDH and branched-chain keto-acid dehydrogenase kinase (BCKDK) are also key enzymes regulating BCAA metabolism(Grimm et al. 2016 ). Furthermore, knockdown of BCKDHA significantly inhibits the proliferation of PDAC cells(Zhu et al. 2020 ). Additionally, the BCKDK-MEK1 axis may be involved in the development of colorectal cancer(Tian et al. 2020 ). BCKDK promotes ovarian cancer proliferation and migration by activating the MEK/ERK signalling pathway(Li et al. 2022a ). Downregulating BCKDK expression can inhibit the migration of breast cancer cells(Xu et al. 2023 ), it can also reduce the in vitro proliferation of NSCLC cells and enhance apoptosis(Wang et al. 2021b ). BCKDH and BCKDK have emerged as attractive targets for treating BCAA-related disorders and cancers. However, further research is needed to fully elucidate their functions and explore their potential as therapeutic targets and biomarkers in oncology.

The mechanisms of tumour nitrogen metabolism described below outline the relevant signalling pathways. BCAA metabolism can regulate the differentiation and activity of immune cells(Yang et al. 2024 ). Research findings indicate that in mice with impaired BCAA degradation, branched-chain amino acids accumulate within CD8 + T cells, thereby generating highly active CD8 + T cells and enhancing anti-tumour immunity(Yao et al. 2023 ). Following BCAA supplementation, the hyperfunction of CD8 + T cells was restored, with synergistic effects observed alongside anti-PD-1 therapy. This indicates BCAAs may serve as adjunctive factors enhancing the clinical efficacy of anti-PD-1 immunotherapy in NSCLC patients. Furthermore, excessive activation of the PI3K/mTOR pathway correlates with lymphocyte depletion and a wound-healing-like immune microenvironment in uterine leiomyosarcoma, thereby facilitating tumour immune evasion(De Wispelaere et al. 2024 ).

Oral administration of BCAAs represents the most direct method of regulating BCAA metabolism. In mice with hepatocellular carcinoma (HCC), supplementation with BCAAs may inhibit the progression of HCC(Takegoshi et al. 2017 ). However, the accumulation of BCAAs within the human body may contribute to the development of certain tumours and even lead to patient mortality. This effect can be mitigated by restricting dietary BCAA intake, though the underlying mechanisms require further investigation(Li et al. 2022b ). BCAAs play a complex role in tumour metabolism. In-depth investigation of their metabolic mechanisms across different tumour types may facilitate the development of precision targeted therapeutics, modulate the tumour immune microenvironment, and enhance the efficacy of tumour immunotherapy.

BCAAs metabolic intermediates (e.g., α-ketoisocaproic acid) may promote the phenotypic plasticity of tumor cells by modulating histone modifications and DNA methylation, thereby enhancing their metastatic potential. In addition, abnormalities in BCAAs metabolism are closely related to immune escape from tumors. Tumor cells evade immune surveillance by depleting BCAAs in the microenvironment and inhibiting the activation and function of T cells(Chi et al. 2022 ; Yao et al. 2023 ). These findings provide new ideas for tumor therapy targeting the metabolism of BCAAs.

Urea cycle and reprogramming of ammonia metabolism

Ammonia excretion occurs primarily through the urea cycle which converts ammonia from amino acid metabolism into non-toxic urea, which subsequently enters the bloodstream and is excreted through the urine. When an abnormal mutation occurs in one of the regulatory enzymes of the urea cycle, it increases the utilization of nitrogen for the synthesis of pyrimidines, enhances the synthesis of nucleotide substances in cancer cells, and promotes the onset and progression of cancer. For example, CPS1 (carbamoylphosphate synthase 1) is a key enzyme in the urea cycle, and its increased expression in colon cancer promotes colon tumor proliferation, migration, invasion, and the ability of 5-Fu drug resistance(Chen et al. 2020 ). CPS1 may enhance tumor cell proliferation, migration, and invasion by decreasing ammonia concentration in the tumor microenvironment and promoting autophagic flow(Zhang et al. 2024a ).

The urea cycle, which mediates ammonia metabolism in tumor cells, is regulated by the tumor suppressor p53. p53 inhibition of the urea cycle leads to ammonia accumulation and tumor growth inhibition, while ammonia accumulation feeds back to activate p53. p53-deficient or mutant tumor cells or mice exhibit high levels of urea cycle metabolizing enzymes (e.g., CPS1)(Li et al. 2019 ). It has also been reported that cMyc, an oncogenic transcription factor in cancer cells, activates glutaminase expression and glutamine metabolism, and increases ammonia accumulation(Wise et al. 2008 )(Table 1. ).

Ammonia is an important source of nitrogen for tumor cell metabolism, which can be recycled to support the high demand for amino acid synthesis in rapidly proliferating cells. It is used by cancer cells for the in vivo synthesis of glutamate and glutamine, metabolism through the urea cycle, dysregulation of the urea cycle involved in pyrimidine synthesis, synthesis of glutamic acid with branched-chain amino acids, and the production of other nitrogen-containing substances such as polyamines and NO. Ammonia assimilation catalyzed by GDH (glutamate dehydrogenase) mediates the stimulation of breast cancer cell growth and proliferation(Spinelli et al. 2017 ). In hepatocellular carcinoma (HCC), β-catenin activation increases ammonia production primarily by stimulating glutamine catabolism. β-catenin/LEF1 activates the transcription of the glutamate dehydrogenase GLUD1 and promotes ammonia utilization, which enhances the production of glutamate, aspartate and proline(Ruiz de Galarreta et al. 2019 ). β-Cyclin/TCF4 induces transcription of the ammonia transporter protein SLC4A11 to excrete excess ammonia. SLC4A11 expression is up-regulated in HCC tumor tissues. Deletion of SLC4A11 induces hepatocellular carcinoma cellular senescence and reduces β-cyclin-driven tumor growth in vivo through the blockade of ammonia excretion(Wang et al. 2024b ). In colorectal cancer, accumulated ammonia reduces the tumor immune response by specifically inhibiting T cell function. Removal of microenvironmental ammonia reactivates T cells, reduces tumor size, and re-sensitizes the tumor to immunotherapy(Bell et al. 2023 ).

Ammonia accumulation may affect tumor immunity in a manner called ammonia death. In the early stages of tumors, effector T cells use ammonia produced by glutamine metabolism to rapidly enter the anabolic pathway and provide precursors for cell growth and proliferation, avoiding an increase in intracellular ammonia concentration. In the late phase when cell proliferation gradually stops, ammonia produced by glutamine metabolism accumulates intracellularly, and intracellular ammonia in effector T cells increases rapidly. The nascent ammonia leaves the mitochondria and enters the lysosome, where it combines with the hydrogen ion H + to form the ammonium ion NH4 + , leading to an increase in lysosomal pH and impairment of its function. The ammonia in the cytosol cannot flow to the lysosomes but returns back to the mitochondria, leading to mitochondrial damage. Damaged mitochondria can be self-cleared through the autophagy pathway, but the elevated lysosomal pH inhibits the enzymatic degradation of autophagic lysosomes, which hinders the clearance of damaged mitochondria, ultimately leading to the death of effector T cells(Zhang et al. 2024a )(Fig. 1 ).

Experiments demonstrate that overexpressing CPS1 or using ammonia scavengers to assist T cells in metabolizing toxic ammonia significantly enhances T cell survival and function within the tumor microenvironment(Zhang et al. 2024a ). Currently, the latest research has designed a bionic nanozyme capable of precisely delivering the inhibitor CB-839 into CD8 + T cells, effectively reducing ammonia accumulation and preventing cell death(Suo et al. 2025 ). These findings provide novel insights and potential clinical applications for T cell-based antitumor therapies. Further scientific research is needed to develop additional therapeutic approaches that enhance T cell-mediated tumor clearance by modulating ammonia levels.

Influence of key enzymes of tumor microenvironment on nitrogen metabolism

Glutaminase (GLS1).

GLS1 plays a crucial role in glutamine metabolism by directly catalyzing the breakdown of glutamine and regulating various cellular functions. It catalyzes the production of various nitrogen-containing substances such as glutamate, ammonia, and nucleotides. In addition to its metabolic functions, GLS1 also regulates cellular reactive oxygen species (ROS) levels. Glutamine depletion or knockdown of the GLS1 gene triggers ROS expression in tumor cells, which may lead to endoplasmic reticulum (ER) stress(Yuan et al. 2015 ). GLS1 expression is up-regulated in a variety of tumor types, including hepatocellular carcinoma, gastric carcinoma, colorectal cancer (CRC), esophageal carcinoma, and lung carcinoma, etc. Its high expression is closely related to tumor aggressiveness, malignancy, and patient prognosis. After using the GLS1 inhibitors BPTES, CB-893 or silencing by siRAN to form siGLS1, the expression activity of GLS1 in tumor cells was weakened, which could significantly inhibit tumor cell migration(Chen et al. 2023 ; Han et al. 2022 ). In papillary thyroid carcinoma, GLS1 is highly expressed, the rapamycin complex 1-mediated signaling pathway is activated, and ULK1 is phosphorylated and inactivated, thereby inhibiting cellular autophagy and promoting tumor cell metastasis(Vidula et al. 2023 ). Inhibition of GLS1 expression has been shown to induce cancer cell cycle arrest. In non-small cell lung cancer cells (NSCLC), the combination of the GLS1 inhibitor BPTES and 5-fluorouracil (5-FU), A549 showed an increase of approximately 20–30% in G1-phase cell cycle arrest, which ultimately resulted in cell death(Lee et al. 2016 ). In addition, inhibition of GLS1 expression may also inhibit tumor angiogenesis(Draoui et al. 2017 ). In addition, transient GLS1 inhibition or lysosomal acidification may induce changes in chromatin accessibility and preservation of epigenetic properties, which may contribute to the long-term persistence of CD8 + T cells in tumors(Madden et al. 2023 ).

Overexpression or hyperactivity of GLS1 is associated with various types of tumors, suggesting that GLS1 may serve as a potential biomarker for tumorigenesis and prognosis(Pan et al. 2015 ). The regulation of GLS1 expression is regulated by various regulatory factors. c-Myc positively regulates the expression of two splice variants of GLS1. Mechanistically, c-Myc promotes glutamate metabolism by directly binding to the promoter regions of the glutamine transporter proteins SLC1A5 and SLC38A5(Wise et al. 2008 ; Yue et al. 2017 ). c-Myc can also upregulate GLS1 by repressing the expression of the antisense IncRNA GLS-AS(Deng et al. 2019 ). Knockdown of c-Myc significantly reduces the expression of GLS1 in human prostate cancer PC3 cells(Gao et al. 2009 ). Another oncogenic transcription factor, c-JUN, also regulates gene expression in GLS1(Lukey et al. 2016 ), may regulate GLS1 transcription and expression through the GSK3a/b pathway, the mTORC1/S6K1 pathway, or indirectly through regulation of miR-23a and miR-23b (Csibi et al. 2025 ; Gao et al. 2009 ; Momcilovic et al. 2018 ). In addition, GLS1 expression is also regulated by hypoxia-inducible factor 1 (HIF-1). The activated transcription factor HIF-1 increases GLS1 mRNA and protein expression under hypoxic conditions. Mechanistically, HIF-1 binds to the hypoxia response element (HRE) in the GLS1 gene to increase GLS1 expression(Okazaki et al. 2017 ; Xiang et al. 2019 ).

Carbamoyl phosphate synthase 1 (CPS1).

CPS1 is a key enzyme in the urea cycle and is directly related to ammonia production.CPS1 is significantly under-expressed in hepatocellular carcinoma tissues and circulating tumor cells, and its down-regulation may be associated with hypermethylation of CpG in its promoter region, which is negatively correlated with the stage and prognosis of HCC(Chen et al. 2024 ; Liu et al. 2011 ). On the one hand, CPS1 blocks diacylglycerol (DAG) biosynthesis by decreasing phosphatidylcholine-specific phospholipase C activity, leading to down-regulation of the DAG/protein kinase C pathway and thus inhibiting invasion and metastasis of HCC cells. On the other hand, CPS1 enhances the m6A modification of solute carrier family 1 member 3 (SLC1A3) mRNA, a key transporter for aspartate uptake, by increasing intracellular S-adenosylmethionine (SAM) to enhance its stability, thereby increasing intracellular transport of aspartate, supplying cellular nutrients, and promoting cell proliferation(Chen et al. 2024 ). However, there are also studies suggesting that CPS1 is upregulated, and CPS1 expression is significantly upregulated in poorly differentiated HCC relative to moderately and highly differentiated HCC, suggesting that CPS1 is associated with the degree of tumor differentiation(Wang et al. 2021a ). However, in intrahepatic cholangiocarcinoma, both CPS1 and CPS1-IT1 expression were upregulated, and knockdown of CPS1 or CPS1-IT1 gene inhibited ICC-9810 cell proliferation and promoted apoptosis, and the increased expression of CPS1 and CPS1-IT1 in cancer tissues suggested that patients had a poor prognosis(Ma et al. 2015 ).

CPS1 interacts with multiple signaling pathway factors or signal transduction pathways such as AMPK, cAMP-PKA-CREB/atf1, PI3K-Akt, etc., which together affect tumor development and patient prognosis(Wu et al. 2019 ; Zhang et al. 2021a , b). In KRAS/LKB1-mutant lung cancer cells, CPS1 maintains the pyrimidine pool and DNA synthesis, and CPS1 expression negatively correlates with LKB1 in human NSCLC.CPS1 enables an unconventional pathway of nitrogen influx from ammonia to pyrimidines, and loss of CPS1 decreases the pyrimidine-to-purine ratio, impairs S-phase progression and induces DNA polymerase arrest and DNA damage(Kim et al. 2017 ).

Glutamine synthetase (GS).

GS catalyzes the formation of glutamine from intracellular glutamate and free ammonia, and tumor cell glutamine synthetase catalyzes the synthesis of endogenous glutamine, which is an important source of substrates for the metabolism of glutamine fermentation and a major metabolic pathway for the metabolite ammonia.GS is up-regulated in cancers such as gliomas, ovarian cancers, and breast cancers, and is known to contribute to the growth and proliferation process of a variety of tumors(Menga et al. 2021 ; Xuan et al. 2023 ; Zhang et al. 2020 ). Decreased GS activity can mediate phenotypic transformation of tumor-associated macrophages and inhibit tumor metastasis(Palmieri et al. 2017 ). When macrophages are in the M0 phenotype, they are transformed into the M1 phenotype by the action of the inflammatory factor interferon and other agonists. The M1 phenotype exhibits an inflammatory response, inhibits angiogenesis, and hampers the process of tumor metastasis, whereas the high expression of GS prompts the M1-phenotype macrophages to become the M1-phenotype macrophages with anti-inflammatory properties by the action of interleukin (IL)−4, IL-13, and IL-10, among others. M2 phenotype with anti-inflammatory effects(Menga et al. 2020 ). GS increases succinate levels in cells, activates HIF-1 to maintain tumor cells in the M2 phenotype, promotes angiogenesis, and increases the toxic effects of T-lymphocytes, which in turn promotes tumor metastasis(Tong et al. 2021 ). In addition, in tumor cells, the oncogene c-myc has been shown to be associated with glutamine addiction. In oral cancer, c-myc acts as an upstream regulator to promote EMT by upregulating the activities of GLS and GS, and inhibition of c-myc expression markedly attenuated the proliferation and migration of oral cancer cells(Wang et al. 2019 ).

Glutamate dehydrogenase 1 (GLUD1).

GLUD1 is the key enzyme that converts glutamate to α-ketoglutarate and releases ammonia. β-Collagen/LEF1 activates GLUD1 transcription and promotes ammonia utilization, thereby supporting tumor cell growth and proliferation. In hepatocellular carcinoma (HCC), β-linker activation increases ammonia production by stimulating glutamine catabolism, and increased expression of GLUD1 promotes ammonia utilization, thereby enhancing glutamate, aspartate, and proline production(Wang et al. 2024b ).

SLC4A11 (ammonia transporter protein).

SLC4A11 is an ammonia transporter protein responsible for expelling excess ammonia from cells. In hepatocellular carcinoma (HCC), SLC4A11 expression is upregulated, and high SLC4A11 expression is associated with poor prognosis and advanced disease stage. Deletion of SLC4A11 induces senescence of hepatocellular carcinoma cells by blocking ammonia efflux and reduces β-conjugated protein-driven tumor growth in vivo(Elaimy et al. 2024 ).

Regulatory mechanisms of tumor nitrogen metabolism and Related Therapies

Transcription factor regulation.

c-Myc is a central regulator of tumor metabolism, which significantly upregulates GLS expression by binding to the promoter region of glutaminase (GLS), driving the catabolism of glutamine to glutamate, which in turn enters the TCA to provide a source of carbon and nitrogen for tumor cells(Wu et al. 2017 ). HIF-1 promotes ammonia production and nitrogen cycling by inhibiting SIRT4 and activating glutamine dehydrogenase (GLUD) in the hypoxic microenvironment, thereby maintaining redox homeostasis in tumor cells. Synergistic interaction of HIF-1 with histone deacetylase (HDAC) dynamically regulates the transcription of GLS1 and enhances glutamine catabolism in response to the stress of hypoxia(Papavassiliou et al. 2023 ).

Signaling pathway regulation: involvement of mTORC1, AMPK and PI3K/Akt.

Signalling pathways serve as a bridge in regulating tumour nitrogen metabolism, participating in nitrogen metabolic reprogramming by integrating nutritional status and growth signals to modulate the activity and expression of nitrogen metabolism-related enzymes.

mTORC1 is a central signaling node in the regulation of cell growth and metabolism, and its activity is regulated by amino acids (especially leucine and glutamine). BCAAs, especially leucine, are the main activators of mTOR(Sciarretta et al. 2018 ). Consequently, some researchers evaluated the growth dependency of osteosarcoma on leucine, discovering that blocking leucine uptake using the leucine structural analogue N-acetylalanine (NALA) leads to mTORC1 downregulation, thereby affecting tumour development(Martin et al. 2020 ). mTORC1, by activating S6K1 and inhibiting 4E-BP1, promotes protein synthesis and nitrogen source utilization(Simcox and Lamming 2022 ). It was found that mTORC1 also affects the expression of aspartate synthase (ASNS) by regulating the expression of ATF4, which supports the nitrogen metabolism requirement of tumor cells(Li et al. 2023b ). In various tumors, the PI3K-AKT-mTOR signaling axis is frequently in an abnormally active state, PI3K/Akt signaling pathway indirectly affects nitrogen metabolism by regulating the activities of mTORC1 and c-Myc(He et al. 2021 ). Akt inhibits the nuclear localization of the FOXO transcription factor by phosphorylating it, thereby down-regulating the expression of enzymes related to the urea cycle, reducing nitrogen waste and promoting the reuse of nitrogen sources(He et al. 2021 ). Including the PI3K/AKT/PTEN and insulin/IGF-1 signaling pathways mentioned earlier (García-Mato et al. 2023 ), as well as epigenetic changes such as the TME and methylation, which may cause abnormal activation of mTOR(Torrence et al. 2021 ). AMPK acts as an energy sensor and reduces the synthesis of nitrogen metabolism-related enzymes by inhibiting mTORC1 activity in a low-energy state, while promoting autophagy to recycle nitrogen sources(González et al. 2020 ). AMPK also limits glutamine metabolism by phosphorylating GLS1 and inhibiting its activity(Zong et al. 2019 ). Cross-regulation of these signaling pathways enables tumor cells to flexibly adjust their nitrogen metabolism strategies in different microenvironments. Active mTOR can stimulate protein synthesis, promote cell cycle progression and cell proliferation, thereby facilitating tumour growth. Consequently, the development of mTOR inhibitors holds significant potential as anti-cancer therapeutics.

Epigenetic regulation: effects of DNA methylation and histone modifications.

Epigenetic mechanisms finely regulate the expression of enzymes related to nitrogen metabolism in tumors by altering chromatin structure and gene expression, and DNA methylation is one of the important epigenetic mechanisms for nitrogen metabolism regulation. It has been found that the hypomethylation status of GLS1 promoter region is closely related to its high expression in tumors, whereas GLS2 expression is limited due to hypermethylation(Bott et al. 2015 ). In addition, histone modifications (e.g., acetylation and methylation) are also involved in the regulation of nitrogen metabolizing enzymes. For example, enrichment of the H3K27ac modification in the GLS1 promoter region is closely associated with its transcriptional activation, whereas the H3K9me3 modification is associated with transcriptional repression of GLS2. Histone deacetylase (HDAC) inhibitors enhance tumor cell proliferation by increasing H3K27ac levels, upregulating GLS1 expression, and promoting glutamine metabolism(Slaughter et al. 2021 ). Dynamic changes in these epigenetic modifications provide an additional level of regulation of tumor nitrogen metabolism.

For epigenetic therapies, traditional approaches such as small-molecule inhibitors of DNA methyltransferases (e.g., DNMTi, HDACi). The latest research has designed anti-Lat4 small interfering RNA complex nanoregulator (AS‐F‐NP) targeting the methionine transporter Lat4. This nanomodulator suppresses the tumor’s malignant evolution by knocking down Lat4 to inhibit the greedy uptake of methionine by tumor cells, while simultaneously restoring the survival and function of immune cells infiltrating the tumor(Su et al. 2025 ). Intervening in tumor nitrogen metabolism through epigenetic mechanisms has emerged as a rapidly advancing research direction. However, multiple challenges remain: systematically understanding the network interactions among multiple nitrogen metabolism pathways, ensuring interventions act with absolute precision on tumor cells, and addressing the highly heterogeneous and plastic metabolic and epigenetic states within the tumor microenvironment that may lead to treatment resistance. These issues require further in-depth scientific investigation.

4. Tumor Microenvironment Regulation.

The tumor microenvironment (TME) is a highly heterogeneous and dynamically evolving ecosystem, where continuous metabolic reprogramming serves as a core feature supporting malignant tumor progression. Recent studies reveal that nitrogen metabolism within the TME is not autonomously regulated by tumor cells but is instead jointly shaped by complex metabolic interactions and competition between tumor cells and various stromal cells (such as cancer-associated fibroblasts, CAFs) and immune cells (particularly tumor-associated macrophages, TAMs)(Li and Simon 2020 ). This intercellular dialogue creates a local environment that promotes tumor growth while suppressing anti-tumor immunity by redistributing nitrogen sources and generating specific metabolites.

Stromal cells, particularly CAFs, directly participate in and regulate tumor nitrogen metabolism by supplying metabolic substrates and clearing waste products. In triple-negative breast cancer, activation of the G protein-coupled estrogen receptor (GPER) in CAFs upregulates glutamine synthase (GLUL) expression through the downstream cAMP/PKA/CREB signaling pathway(He et al. 2024 ). In pancreatic ductal adenocarcinoma, activated pancreatic stellate cells (the primary source of CAFs) secrete large amounts of alanine through autophagy, supplying it as a major carbon and nitrogen source to tumor cells, thereby alleviating the latter’s dependence on glucose and glutamine. Additionally, CAFs deliver metabolites such as amino acids and lipids to cancer cells via exosomes or directly secrete reduced glutathione and cysteine, helping cancer cells resist oxidative stress and mediate treatment resistance(Li and Simon 2020 ). CAFs and other stromal cells metabolically produce ammonia, which accumulates in TME and can be specifically utilized by regulatory T cells (Tregs). Tregs detoxify ammonia by activating argininosuccinatelyase(ASL), and divert the intermediate product into the polyamine synthesis pathway to generate spermine. Spermine directly activates peroxisome proliferators-activated receptors(PPARγ), systemically enhancing Tregs’ mitochondrial oxidative phosphorylation capacity, thereby substantially boosting their immunosuppressive function(Gu et al. 2025 ).

The core regulation of nitrogen metabolism by TAMs revolves around the competitive utilization of arginine. Pro-inflammatory M1 TAMs, which possess potential anti-tumor functions, highly express inducible nitric oxide synthase (iNOS), converting arginine into nitric oxide (NO) and citrulline. In contrast, pro-tumor, immunosuppressive M2 TAMs highly express arginase 1 (ARG1), hydrolyzing arginine into ornithine and urea. Active ARG1 exerts dual tumor-promoting effects: first, it directly depletes arginine essential for T cell activation in the microenvironment, leading to T cell functional suppression or even apoptosis; second, the resulting ornithine serves as a precursor for polyamine synthesis, which further stimulates tumor cell proliferation and suppresses immune responses(Jin et al. 2025 ).

5. Clinical drug or clinical trial research related to nitrogen metabolism.

Regarding the current research on tumor nitrogen metabolism, there are still many related clinical trials underway to explore the efficacy of nitrogen metabolism-related drugs and targets. We select a number of recent progress and summary in Table 2 ( https://clinicaltrials.gov// ), which shows a promising therapeutic outcomes.

Conclusions and outlook

This review provides a comprehensive overview of the nitrogen metabolism characteristics of tumors and the latest research advances in nitrogen metabolism-targeted therapies. By focusing on tumor nitrogen metabolism features, it reveals the specificity and diversity of nitrogen metabolism within the tumor microenvironment, identifies potential therapeutic strategies targeting these characteristics, and suggests new directions for cancer treatment.

Figure 2 demonstrates many amino acid metabolisms associated with nitrogen metabolism. A deeper understanding of nitrogen metabolism-related proteins, key enzymes, metabolites, signaling pathways, and other factors will enhance our knowledge of tumor nitrogen metabolism. In Fig. 3 , we summarize the key dysregulated molecules in distinct tumor nitrogen metabolism pathways. These molecules are associated with cancer development and progression and may serve as potential therapeutic targets. Understanding these molecules facilitates the development of personalized medicine and targeted cancer therapies.

Numerous clinical studies targeting nitrogen metabolism are currently underway. In the future, as our understanding of nitrogen metabolism in cancer patients deepens and with the ongoing refinement and application of tumor therapies, increasingly sophisticated treatment strategies and novel drug candidates are anticipated to emerge. These advancements are expected to ultimately improve clinical outcomes and quality of life for cancer patients.

Acknowledgements

We thank Biorender for providing high-quality image material for this study. We are grateful to Biorender for providing the resources and tools that enriched our research.

Author contributions

Jiaqi Fang conceived the structure of the manuscript; Jiaqi Fang retrieved the relevant paper and finished the manuscript including figures and tables; Jiaqi Fang, Jing Ling, Yanbin Wang, Yongbiao Huang, Zhe Cao, Yanmei Zou, Hua Xiong revised the manuscript. All authors contributed to the preparation of this manuscript. All authors have read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China under grant 82272902 and the National Natural Science Foundation of Hubei Province under grant 2024AFD424, the National Natural Science Foundation of Hubei Province under grant 2025AFD793.

Data availability

Data will be made available on request.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

Not applicable.

Consent for publication

Not applicable.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yanmei Zou, Hua Xiong contributed equally to this work.

Contributor Information

Yanmei Zou, Email: whtjzym@tjh.tjmu.edu.cn.

Hua Xiong, Email: cnhxiong@tjh.tjmu.edu.cn.

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Associated Data

Data Availability Statement

Data will be made available on request.