Amino acids metabolism: a potential target for cancer treatment.

Background

Cancer is a non-infectious disease that seriously affects human life [ 1 ]. Elucidating the pathophysiological characteristics and molecular mechanisms underlying cancer development and progression is crucial for identifying more effective diagnostic and therapeutic strategies. An important hallmark of cancer is a series of metabolic reprogramming events that enable cancer cells to meet their biosynthetic and bioenergetic demands [ 2 ]. In the 1920 s, Warburg first demonstrated that cancer cells can increase their glucose consumption and produce lactate to fulfill their energy requirements, even under aerobic conditions [ 3 ]. Recent studies on metabolic reprogramming have made substantial progress. In addition to glucose metabolism, amino acids metabolism also plays an important role in providing energy for tumor cell proliferation and further affects the metabolism of other nutrients [ 4 ].

Amino acids, essential nutrients, and metabolic hubs, integrate diverse processes such as central carbon metabolism and autophagy. They promote cell growth not only by serving as anaplerotic substrates for central carbon metabolism but also by activating mechanistic target of rapamycin complex 1 (mTORC1) signaling to suppress autophagy. Numerous studies have shown that amino acids are important metabolites associated with tumor development [ 5 ]. Most cancer cells, such as those with hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer, typically exhibit a preference for specific amino acids to maintain high proliferative activity, promote tumor growth, facilitate immune evasion, and induce chemotherapy resistance [ 4 , 6 ]. In addition, some amino acids have been found to have essential functions in the activation of immune cells, and the deficiency of certain amino acids in the tumor microenvironment (TME) will correspondingly inhibit immune functions [ 7 ]. Therefore, these studies suggest that amino acids can provide energy during tumor cell proliferation and participate in the tumor immune process by regulating the function of immune cells.

Since tumor cells are more sensitive to changes in amino acid levels in serum than normal cells, exogenous intervention of amino acid content in TME is an effective treatment [ 1 ]. Modulating the metabolism of a specific amino acid can be achieved by regulating the anabolic and catabolic enzymes of amino acids, as well as directly manipulating the supply of exogenous amino acids [ 8 , 9 ]. Moreover, to achieve better therapy effects of amino acids, nanomaterials are increasingly being applied. Here, we summarize various potential methods for cancer treatment targeting amino acids, including metabolic enzymes of amino acids, enzyme inhibitors, dietary interventions, and nanomedicine applications.

Amino acids and central carbon metabolism

Numerous studies have shown that central carbon metabolism is significantly aberrant in cancer cells compared to normal cells [ 10 ]. Classically, the study of cancer metabolism has focused on central carbon metabolism. Beyond serving as substrates for protein synthesis, amino acids often act as integral regulators of central carbon metabolism, including glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, thereby fueling bioenergetics and anabolic processes through multiple mechanisms [ 11 , 12 ] (Fig. 1 ). Although glucose is well-established as a prominent energy source for cancer growth, amino acids also serve as crucial fuels that support cancer progression. Therefore, understanding the functions and regulatory mechanisms of amino acids in central carbon metabolism may facilitate the development of novel therapeutic strategies targeting tumor metabolism.

Glycolysis, the TCA cycle, and oxidative phosphorylation

Glutamine

Glutamine is critical for connecting nitrogen metabolism and central carbon metabolism. It can be converted into glutamate by glutaminase (GLS), which subsequently participates in multiple metabolic pathways, including GSH synthesis, proline synthesis, and the TCA cycle [ 13 ].

In cellular metabolism, anaplerosis and cataplerosis refer to the dynamic balance of metabolites entering and exiting the TCA cycle to stabilize the intermediate pool. Studies have indicated that the anaplerotic role of glutamine is crucial. Glutaminolysis generates α-ketoglutarate (α-KG) and subsequently oxaloacetate (OAA), and they can fuel the TCA cycle as intermediates, stabilizing the carboxylate pool in the TCA cycle and supporting cellular oxidative phosphorylation [ 14 , 15 ]. Additionally, glutamine provides both carbon and nitrogen sources for the synthesis of other amino acids and nucleotides. For example, glutamine is required for de novo asparagine synthesis. GLS can catalyze glutamine into glutamate, which can then enter the TCA cycle and the respiratory chain to generate aspartate. Studies have shown that inhibiting glutaminolysis severely reduces TCA cycle intermediates, and glucose-derived anaplerosis is unable to compensate for this loss, ultimately impairing cell proliferation [ 16 ]. Overall, glutamine-derived anaplerosis not only sustains energy but also provides essential precursors for macromolecular biosynthesis, which is indispensable for the rapid proliferation of cancer cells. In cancer cells, glutamine is a major amino acid. Glutamine-derived α-KG is oxidized to succinate and fumarate. These metabolites maintain the TCA cycle in cancer cells by providing ATP, NADH, and FADH 2 , and by acting as oncometabolites, thereby supporting cancer growth [ 14 , 17 ]. For example, studies found that progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle [ 18 ]. Deprivation of glutamine or inhibition of GLS can effectively reduce intermediates in TCA cycle and suppress endothelial and tumor cell proliferation [ 16 , 19 ].

Asparagine

Asparagine and aspartate can be transformed into each other via asparaginase and asparagine synthetase (ASNS), and further contribute as TCA cycle intermediates to the synthesis of macromolecules such as nucleotides and lipids, thereby supporting cellular proliferation demands [ 20 , 21 ]. This is crucial for maintaining TCA cycle flux under glucose deprivation or other metabolic stress conditions, thereby ensuring sustained energy production [ 22 ]. Moreover, asparagine stimulated the mTORC1 pathway, which promoted the expression of thermogenic genes and key enzymes in glycolysis, thereby affecting systemic energy homeostasis [ 22 ].

In addition, studies have shown that asparagine availability is critical for tumor cell adaptation and growth. Asparagine metabolism may confer metabolic plasticity to cancer cells, enabling them to reprogram their metabolic pathways in response to nutrient deprivation or therapeutic stress, thereby promoting treatment resistance [ 23 ]. Therefore, inhibiting asparagine can impede tumor progression by disrupting central carbon metabolism.

Serine and Glycine

The serine biosynthesis pathway is a component of glycolysis. The serine synthesis pathway (SSP) utilizes the glycolytic intermediate 3-phosphoglycerate (3-PG), which is converted by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) into serine [ 24 ]. Serine can be converted to glycine by serine hydroxymethyltransferase (SHMT) [ 25 ]. The serine accumulation further accelerates glycolytic flux, establishing a positive feedback loop. Glycolysis provides ATP and energy in most cells, and cancer cells extensively use glycolysis to sustain anabolism, which is necessary for tumor growth [ 26 ]. Furthermore, the SSP plays a substantial role in replenishing the TCA cycle, accounting for approximately half of its anaplerotic flux, and serine/glycine restriction impacts the TCA cycle [ 27 , 28 ].

Multiple studies have shown that in various cancers, the gene expression of PHGDH is significantly up-regulated, leading to the overexpression of related enzymes, subsequently increasing the synthesis of serine and glycine, thereby supporting the proliferation of tumor cells [ 27 ]. Moreover, serine supports aerobic glycolysis and lactate production by allosterically fine-tuning the glycolytic rate in cancer cells to support cancer cell growth and survival [ 29 , 30 ].

Redox homeostasis and NADPH generation

Maintaining redox homeostasis is critical in central carbon metabolism and can provide energy and defend against pathogens. Nicotinamide adenine dinucleotide phosphate (NADPH) and GSH are central metabolic regulators. They not only provide reducing power for anabolic processes but also maintain redox balance by eliminating reactive oxygen species (ROS) [ 31 , 32 ]. Importantly, amino acids play essential roles in cellular redox homeostasis by regulating GSH and NADPH. For example, cysteine, glutamate, and glycine serve as precursors for GSH biosynthesis [ 33 ]. Recent studies have demonstrated that serine/glycine-driven one-carbon metabolism generates substantial amounts of NADPH and GSH in proliferating cells, thereby partially compensating for the reduced TCA cycle activity [ 34 – 36 ]. Moreover, glutaminolysis critically contributes to maintaining redox homeostasis by promoting GSH synthesis and elevating NADPH levels [ 37 ]. Other amino acids, such as asparagine and cysteine, also play widespread roles in regulating redox balance [ 38 , 39 ].

Redox dysfunction is closely implicated in the development and pathology of many metabolic diseases, including cancer [ 40 – 42 ]. In tumors, metabolic reprogramming often disrupts redox homeostasis, leading to elevated oxidative stress [ 43 – 45 ]. Therefore, to maintain this challenge, cancer cells enhance their antioxidant capacity through multiple mechanisms, including the upregulation of antioxidant biosynthesis, such as GSH and NADPH [ 46 ].

Amino acid metabolism contributes substantially to redox homeostasis of cancer. For instance, pancreatic ductal adenocarcinoma (PDAC) cells strongly depend on glutamine to sustain a reduced state [ 47 ]. Glutamine deprivation increases ROS accumulation and reduces GSH levels, and sensitizes cells to oxidative stress, thereby suppressing proliferation and slowing tumor growth [ 47 – 49 ]. Furthermore, serine-derived NADPH not only supports redox homeostasis but also fuels lipid biosynthesis. It is beneficial for the development of various cancers, such as liver cancer and melanoma. Meanwhile, it also promotes cancer cell survival, invasion, and metastasis under stress conditions [ 50 , 51 ]. In addition, serine can alleviate oxidative stress via supporting GSH synthesis [ 52 ]. In breast cancer and glioblastoma, knockdown or inhibition of PHGDH can impair serine metabolism, reduce NADPH production, elevate ROS levels, disrupt mitochondrial redox balance, ultimately triggering apoptosis and markedly suppressing cell proliferation [ 53 , 54 ]. Moreover, cysteine can maintain the tumor redox balance and increase drug resistance [ 55 ]. Inhibition of cysteine uptake reduces cell viability by triggering uncontrolled oxidative stress, ultimately leading to cancer cell death [ 56 ].

Overall, amino acid metabolism plays a crucial role in the central carbon cycle, oxidative stress, and replenishing reducing power, thereby influencing tumor progression. Therefore, targeting the central amino acid metabolism to disrupt the tumor metabolic reprogramming and redox homeostasis may represent a promising strategy for cancer treatment.

The interplay between autophagy and amino acid metabolism in cancer

Amino acids as core regulatory signals of autophagy

Autophagy is a conserved cellular degradation and recycling process that maintains energy homeostasis and cell survival by breaking down and reusing cellular components such as proteins and organelles [ 57 ]. It enables cells to adapt to stress conditions. Nutrient deprivation is one of the most common triggers of autophagy, with AMP-activated protein kinase (AMPK) and mTORC1 serving as key nutrient sensors. AMPK and mTORC1 monitor cellular energy and amino acid pools, and mTORC1 negatively regulates autophagy [ 58 ]. Energy depletion increases the AMP/ATP ratio, which activates AMPK and suppresses mTORC1 activity, thereby inducing autophagy [ 59 ]. In addition, general control nonderepressible 2 (GCN2) also plays an important role in autophagy induction [ 60 , 61 ].

Studies have found that amino acids such as arginine, leucine, glutamine, and methionine not only serve as essential nutrients for cell survival but also regulate autophagy by modulating mTORC1, GCN2, and AMPK signaling [ 61 , 62 ]. Typically, elevation of amino acid abundance suppresses autophagy, while moderate amino acid deprivation induces autophagy to protect cells [ 63 , 64 ]. For example, arginine supplementation enhances mTOR signaling and reverses GCN2 phosphorylation to inhibit autophagy, in the meantime, arginine deprivation activates AMPK to inhibit mTORC1 and induce autophagy through the GCN2-ATF4 signaling pathway [ 61 , 65 , 66 ]. Glutamine also plays a crucial role in autophagy regulation. It is required for mTORC1 signaling and suppresses autophagy, whereas enhanced glutamine synthesis can inhibit mTORC1 activity and induce autophagy, promoting cell survival [ 67 – 69 ]. Conversely, glutamine starvation upregulates SLC7A5 expression, increases intracellular leucine uptake, activates mTORC1, and suppresses autophagy [ 70 ]. Moreover, glutamine catabolism generates metabolites that exert distinct regulatory effects on autophagy. Specifically, GLS catalyzed glutamine degradation produces α-KG and ammonia. α-KG stimulates RAG-GTP binding, activates mTORC1, and inhibits autophagy, while ammonia induces mTORC1-independent autophagy [ 71 ]. Inhibition of GLS reduces ammonia production and suppresses ammonia-induced autophagy [ 72 ]. Among amino acids, leucine is the most potent autophagy suppressor in most cell types. Leucine acts as a strong positive regulator of mTORC1 signaling and inhibits autophagy by suppressing p62 degradation and LC3-II accumulation [ 73 ]. Conversely, leucine deprivation effectively induces autophagy [ 74 , 75 ]. Methionine levels are also closely linked to autophagy regulation. In gastric cancer stem cells, methionine suppresses autophagy by suppressing RAB37 expression via enhancing its methylation and suppressing RAB37 activity via the miR-200b/PKC axis, thus repressing RAB37-mediated autophagy. Consuming methionine can induce autophagy [ 76 ]. Methionine restriction (MR) can promote cell apoptosis and autophagy via up-regulating the expression of SNHG5 and down-regulating miR-20a in gastric cancer [ 77 ].

Autophagy and amino acid regulation under nutrient deprivation

Under nutrient stress or starvation, to overcome metabolic stress caused by limited nutrient and oxygen availability, cells suppress mTORC1 activity and induce autophagy, degrading cellular components to recycle nutrients and sustain energy metabolism [ 78 , 79 ]. Importantly, autophagy is essential for maintaining the intracellular amino acid pool under nutrient deprivation [ 80 ]. Through lysosomal degradation, extensive transamination and deamination reactions, autophagy provides nitrogen to sustain glutamate and aspartate synthesis, which supports macromolecular synthesis, maintains mitochondrial oxidative phosphorylation, and promotes cell survival [ 81 – 83 ]. Moreover, autophagy and glutamine utilization are mutually regulated. Activation of autophagy and increased glutamine synthesis are key adaptive mechanisms for maintaining amino acid balance. Glutamine metabolism restores mTORC1 activity in an autophagy-dependent manner during prolonged amino acid starvation, allowing rapid exit from autophagy and resumption of cell growth upon nutrient recovery [ 84 ]. In addition, autophagy recycles serine, which subsequently enters one-carbon metabolism to support mitochondrial protein synthesis, enabling rapid adaptation to respiratory growth [ 85 ].

Functions of the autophagy/amino acid crosstalk in cancer

Cancer cells often exist in nutrition-deficient and hypoxic microenvironments. To cope with this metabolic stress, tumor cells activate autophagy to recycle nutrients and maintain energy homeostasis, enabling their adaptation and survival under harsh conditions and supporting tumor growth [ 82 , 86 – 90 ]. Interestingly, autophagy exerts dual roles in cancer progression. In early tumorigenesis, autophagy suppresses tumor growth by degrading cellular components. However, in advanced tumors, autophagy is frequently upregulated as an adaptive mechanism that maintains energy homeostasis and promotes tumor growth, metastasis, and therapy resistance [ 91 ]. Thus, depending on tumor stage and context, autophagy can either inhibit or support tumor progression. Given the regulatory effects of amino acids on autophagy, targeting tumor-specific amino acid metabolism to modulate autophagy may yield either tumor-promoting or tumor-suppressive outcomes, offering a promising therapeutic strategy when applied rationally.

Autophagy promotes tumor progression

In many tumors, including melanoma, glioblastoma, prostate cancer, and breast cancer, amino acid deprivation activates autophagy as an adaptive survival mechanism that maintains metabolic homeostasis, thereby promoting tumor progression and resistance [ 92 – 95 ]. Suppression of mTORC1 during nutrient imbalance enhances autophagy and prevents glutamate-dependent apoptosis, supporting cancer cell survival [ 96 ]. Ammonia generated from glutamine catabolism induces mTORC1-independent autophagy and reduces osteosarcoma cell death [ 97 ]. Under glutamine deprivation, autophagy protects prostate cancer cells from stress, whereas autophagy inhibition sensitizes them to radiotherapy [ 98 , 99 ]. Moreover, arginine supplementation or enhanced glutamine metabolism suppresses autophagy and promotes cancer cell death [ 100 , 101 ].

Autophagy suppresses tumor growth

In certain contexts, excessive or prolonged activation of autophagy triggered by severe amino acid starvation surpasses its protective capacity and induces cancer cell death. For example, arginine-succinate synthase 1 (ASS1), a key enzyme in arginine biosynthesis, is downregulated in many solid tumors. In ASS1-deficient melanoma and breast cancer, sustained arginine deprivation impairs mitochondrial respiration, induces cytotoxic autophagy, and promotes cancer cell death [ 102 , 103 ]. Arginine deaminase (ADI) can restrict arginine metabolism and then induce autophagy and suppress prostate cancer [ 104 ]. Additionally, glioma cells exhibit high methionine dependence; methionine deprivation elevates ROS levels and induces autophagy, inhibiting glioma proliferation both in vitro and in vivo [ 105 ].

These findings highlight the close interplay between autophagy and amino acid metabolism in cancer (Fig. 2 ). Modulating autophagy/amino acid crosstalk represents a potential therapeutic strategy. However, several challenges remain. In clinical cancer therapy, autophagy inhibition appears to enhance therapeutic efficacy, whereas therapy-induced autophagy often acts as a resistance mechanism [ 106 ]. Most tumors exhibit increased amino acid uptake and utilization; thus, many amino acid-targeted therapies aim to restrict amino acid metabolism, which in turn induces autophagy. Dual inhibition of amino acid metabolism and autophagy has demonstrated synergistic effects, improving patient outcomes with lower toxicity and fewer adverse effects [ 99 , 107 – 109 ]. Given the high amino acid dependency of tumor cells, rational design of novel amino acid metabolism inhibitors, combined with optimized autophagy inhibitors, can provide more effective therapeutic options. Moreover, both the beneficial and detrimental consequences of autophagy modulation should be carefully considered to anticipate and counteract adverse effects and resistance mechanisms. A deeper understanding of how autophagy supports cancer metabolism will offer new insights into improving cancer therapy.

Metabolic enzymes of amino acids

The level of amino acids is influenced by various factors, especially enzyme activity. Metabolic enzymes of amino acid balance the catabolism and biological transformation of amino acids in cells through dynamic regulation of metabolites, and multiple metabolic enzymes of amino acids therapies have demonstrated efficacy in cancer treatment [ 110 ] (Table 1 ). In this section, we mainly focus on elucidating the effects of several key metabolizing enzymes of amino acids in tumors (Fig. 3 ) and summarizing major enzyme inhibitors that can impede tumor progression (Table 2 ).

Asparagine

Asparagine is a non-essential amino acid (NEAA). Studies have found that high levels of asparagine can maintain tumor cell survival by inhibiting AMPK-mediated p53 activation and activating the mTOR pathway, while asparagine restriction reduces the expression of Myc protein and inhibits tumor metastasis [ 111 – 113 ].

Recently, increasing evidence has highlighted the critical role of asparagine in anti-tumor immunity. Asparagine restriction has been shown to enhance the metabolic adaptability and antitumor function of CD8⁺ T cells through an Nrf2-dependent stress response [ 114 ]. In addition, asparagine can inhibit IFN-α signaling and promote immune escape in bladder cancer, thereby suppressing anti-tumor immune responses [ 115 ]. The combination of asparagine restriction with anti-programmed cell death ligand 1 (PD-L1) antibody therapy exhibited superior anti-tumor efficacy compared with anti-PD-L1 monotherapy [ 116 ].

Studies found that intracellular asparagine can be an amino acid exchange factor. Asparagine can exchange with extracellular EAAs to modulate the uptake of amino acids, especially arginine, serine, and histidine [ 117 ]. This exchange function further coordinates the synthesis of proteins and nucleotides, and influences tumor cell proliferation by regulating mTORC1 activity [ 117 , 118 ]. The above evidence suggests that asparagine metabolism is critical for the growth and survival of cancer cells. Asparagine restriction is a promising and clinically relevant strategy to inhibit tumor growth and enhance immunotherapy against multiple cancer types. The synthesis and degradation of asparagine are primarily regulated by ASNS and asparaginase. Therefore, targeting these key enzymes can provide new strategies for the development of anti-tumor drugs.

L-asparaginase

L-asparaginase is one of the earliest amino acid-based enzyme therapies for cancer treatment. Several L-asparaginase preparations have been approved by the European Commission or the Food and Drug Administration (FDA), primarily for the treatment of hematologic malignancies like acute lymphoblastic leukemia (ALL) [ 119 , 120 ].

In recent years, studies have shown that L-asparaginase possesses a wide range of applications and shows potential in treating cancers beyond hematological cancers. For instance, L-asparaginase is markedly toxic to CRC by decreasing asparagine metabolism [ 121 ]. In breast cancer and lung cancer models, L-asparaginase remarkably regulates apoptosis pathways and activates autophagy by reducing the availability of asparagine, effectively inhibiting tumor cell proliferation [ 122 ]. Moreover, a developed nanoparticle (NP) for releasing L-asparaginase, which can substantially suppress the epithelial-mesenchymal transition and growth of primary and relapsed cancers in CRC and triple-negative breast cancer [ 123 ].

Nevertheless, L-asparaginase has some adverse reactions such as hypersensitivity reactions, pancreatitis, liver dysfunction, and thrombosis [ 124 ]. To address these issues, improved formulations have been developed, such as the L-asparaginase variant ABD-ErA-TM, designed by Van Trimpont et al., which has shown reduced toxicity in mouse models [ 125 ]. Overall, L-asparaginase remains a highly promising anti-tumor drug. Future efforts will focus on optimizing its therapeutic efficacy and reducing adverse reactions to expand its application in cancer treatment.

ASNS

ASNS is an essential enzyme in the asparagine metabolic pathway, catalyzing the conversion of aspartate to asparagine. Multiple studies have indicated that ASNS is involved in some oncogenic pathways, exhibiting abnormally high expression in various tumor tissues to meet the asparagine demands of tumor cells [ 126 , 127 ]. The overexpression of ASNS can promote tumor progression through multiple mechanisms. For instance, overexpression of ASNS can increase asparagine levels, then promoting tumor growth and enhancing tumor metastasis through activating the mTOR pathway and stabilizing the β-catenin complex that activates the Wnt signaling pathway [ 113 , 127 ]. Additionally, overexpression of ASNS also induces the sensitivity of pancreatic cancer cells to apoptosis under glucose deprivation and cisplatin by suppressing the activation of JNK/SAPK [ 128 ].

Several studies have confirmed that ASNS inhibition can reduce asparagine levels and effectively suppress the malignant phenotype of tumors. For example, in breast cancer, ASNS knockdown can inhibit cell proliferation and colony formation by increasing cell autophagy and reducing mTORC1 activity [ 117 , 127 , 129 ]. In osteosarcoma, ASNS inhibition decreases osteosarcoma cell aggressiveness by weakening the effects of NUCKS1 on cell growth and migration [ 9 ]. Moreover, ASNS inhibition can enhance the sensitivity of anti-tumor drugs such as cisplatin and artemisinin, thereby improving anti-tumor efficacy. This is achieved by suppressing the activation of JNK/SAPK, disrupting the amino acids metabolism, and activating endoplasmic reticulum stress [ 130 , 131 ]. More importantly, recent studies have demonstrated that depletion of ASNS limits tumor growth in a CD8 + T cell-dependent manner and boosts immunotherapy efficacy [ 115 ].

Meanwhile, various developed ASNS inhibitors have shown anti-cancer effects. For example, in lung cancer, bisabosqual A shows promising efficacy by inducing oxidative stress and inhibiting autophagy. In addition, the combination of bisabosqual A with L-asparaginase, rapamycin, and torin-1 has been shown to have significant synergistic anti-tumor effects [ 132 ]. Tumors with high ASNS expression exhibit reduced responsiveness to immune checkpoint inhibitor therapy, and knockdown of ASNS promotes the programmed cell death protein 1 (PD-1) blockade efficacy [ 115 ]. Combining ASNS inhibition with anti-PD-1 treatment may synergistically suppress tumor growth. These findings suggest that targeting ASNS can not only inhibit tumor cell proliferation but also enhance anti-tumor immune responses, thereby suppressing tumor growth. Targeting ASNS also exerts a synergistic effect by increasing the efficacy of existing anti-cancer agents, offering new strategies for cancer therapy and combination treatment.

Glutamine

Glutamine is the most abundant amino acid in human blood and is crucial for nucleotide biosynthesis, driving oxidative phosphorylation to provide energy [ 131 ]. Normal cells synthesize glutamine through GLS, whereas most cancer cells, due to abnormal proliferation demands, typically increase their uptake and metabolism of glutamine [ 132 , 133 ].

Growing evidence suggests that glutamine metabolism plays a critical role in immune regulation. Immune cells require glutamine for proliferation and activation during immune reaction, which in turn influences the nature and efficacy of the immune response [ 132 , 134 ]. Notably, within TME, cancer cells and immune cells compete for the limited availability of glutamine [ 134 ]. Because cancer cells typically possess a higher capacity for glutamine uptake and overexpress GLS to decompose more glutamine to obtain the energy for proliferation, this metabolic competition often results in glutamine deprivation in immune cells, thereby impairing anti-tumor immune functions and weakening immune surveillance [ 134 ].

Given the complex roles of glutamine metabolism, selectively targeting glutamine metabolism in cancer cells has emerged as a promising therapeutic strategy. This approach offers dual therapeutic benefits: directly inhibiting tumor growth while restoring T cell immune function [ 132 , 135 ]. Interestingly, glutamine starvation may have more direct consequences on tumor cell survival than T cells [ 136 ]. Studies have shown that glutamine deprivation can sensitize cancer cells to radiotherapy. Glutamine deprivation combined with radiotherapy boosts CD47 expression, DNA damage, and oxidative stress, leading to tumor regression [ 131 , 137 ]. A recent study reported that the inhibition of glutamine utilization increased PD-L1 levels in cancer cells, thereby sensitizing cancer cells to PD-1/PD-L1 blockade therapy [ 138 ]. Conversely, glutamine supplementation can inhibit tumor growth by enhancing CD8⁺ T cell-mediated immunity [ 139 ]. Furthermore, the recent study suggests that selectively inhibiting glutamine metabolism in tumor cells can alleviate the competitive glutamine stress within the TME, thereby making more glutamine available to immune cells and promoting anti-tumor immunity [ 132 ]. The evidence indicates that targeting glutamine metabolism holds significant promise for inhibiting tumor growth and enhancing anti-tumor immunity in cancer therapy. Since the synthesis and degradation of glutamine are catalyzed by glutamine synthetase (GS) and GLS, respectively [ 136 ], we will discuss the effect of GLS and GS on tumors and explore strategies for cancer.

GLS

As the key enzyme catalyzing the conversion of glutamine to glutamate, GLS exists in two functionally distinct subtypes: the tumor-promoting renal GLS1 and the tumor-suppressive hepatic GLS [ 140 ]. GLS1 is significantly expressed in multiple cancers, including colorectal, breast, and other cancers, and facilitates tumor metastasis by coordinating the breakdown of glutamine and promoting cell proliferation [ 141 – 143 ]. Notably, specific inhibition of GLS1 in tumor cells not only directly impairs tumor growth and metastasis but also significantly enhances the infiltration and activity of CD8 + T cells through increasing interstitial glutamine uptake, GSH synthesis, and granzyme B in cytotoxic T cells [ 132 ].

At present, substantial progress has been made in the development of GLS1 inhibitors. CB-839 has demonstrated good tolerability and anti-tumor activity as a monotherapy or in combination with agents such as paclitaxel and everolimus in phase I clinical trials ( NCT02071862 ) [ 144 ]. Moreover, when combined with immune checkpoint blockade (ICB), co-administration of CB-839 with ICB prevents PD-L1 antibody-induced CD8⁺ T cell exhaustion, thereby suppressing ovarian cancer progression [ 145 ]. Another GLS1 inhibitor, such as compound 968, has been shown to significantly inhibit GLS1 expression and proliferation of ovarian cancer in a dose-dependent manner [ 146 ].

In contrast to GLS1, GLS2 is often downregulated in highly malignant cancers [ 147 ]. Overexpression of GLS2 exerts tumor-suppressive effects through multiple mechanisms, significantly reducing tumor cell colony formation, inhibiting cancer migration, inducing apoptosis, and improving the survival rate [ 148 – 150 ]. Recent studies have found that GLS2 inhibited the migration of HCC cells [ 150 ]. Mechanistically, GLS2 can facilitate the conversion of glutamate to a-KG and increase lipid reactive ROS production, then promoting ferroptosis and finally limiting HCC in vivo [ 147 ]. Additionally, as a p53 target, GLS2 mediates p53 function in metastasis suppression through binding to small GTPase Rac1 [ 150 ].

These findings suggest that the differential regulation of GLS1 and GLS2 may offer a valuable therapeutic approach for certain types of cancer. Further studies should explore the regulatory molecular mechanisms in order to update GLS1 inhibitors and develop effective GLS2-activating strategies.

GS

GS catalyzes the de novo synthesis of glutamine to promote tumor growth and often exhibits pro-tumoral features by synthesizing glutamine and supporting nucleotide synthesis. GS is highly expressed in liver, lung, and prostate cancer, and provides glutamine to cancer cells to maintain the glutamine level [ 151 – 153 ]. Furthermore, a study shows that GS can drive tumor progression via promoting APC/C-mediated tumor cell mitosis [ 154 ]. Inhibiting GS can reduce glutamine levels and alter other cellular functions to suppress cancer cell growth [ 155 , 156 ]. Additionally, depleting GS will impact nucleotide metabolism and tumor proliferation, and enhance the efficacy of radiotherapy and chemotherapy [ 154 ]. Regarding immune cells, pharmacological inhibition of GS can induce lymphocyte recruitment and accumulation of cytotoxic CD8 + T cells and inhibit cancer cell metastasis, suggesting that GS inhibition may be an approach for activating anti-tumor immunity [ 156 ]. Several compounds, such as methionine sulfoximine, phosphinothricin, and alendronate, can act as GS inhibitors and have shown potential anti-cancer activity against lung and breast cancer [ 151 , 157 ]. Consequently, the above evidence indicates that GS can be a promising therapeutic target against cancer.

Arginine

Arginine is recognized as an essential amino acid (EAA) that plays a critical role in many physiological processes, including cell division and urea metabolism. Studies have demonstrated that high levels of arginine can not only promote tumor proliferation, metabolic reprogramming, and oncogenicity, but also enhance the resistance and metastatic potential of cancer cells [ 4 , 158 , 159 ]. Meanwhile, deprivation of arginine has been shown to inhibit tumor growth significantly [ 102 ]. In addition, studies have revealed distinct differences in arginine metabolism between tumor cells and immune cells, contributing to the suppression of anti-tumor immunity. For example, the expression of arginine-metabolic enzymes differs markedly between tumor cells and immune cells. Tumor cells typically exhibit high expression of arginine biosynthetic enzymes, such as ASS1, to meet their elevated arginine demands [ 160 ]. In contrast, certain immunosuppressive cells, including M2-polarized macrophages and myeloid-derived suppressor cells (MDSCs), highly express arginase 1 (ARG1), which depletes arginine in the TME and ultimately suppresses the proliferation and effector function of cytotoxic T lymphocytes [ 161 , 162 ].

Arginine plays an important role in the function and growth of T cells. Arginine induced a metabolic shift in activated T cells from glycolysis to oxidative phosphorylation, promoting the generation of T cells with higher survival capacity and anti-tumor activity [ 162 ]. However, a competition for arginine exists between tumor cells and T cells. In TME, most cancer capture arginine, resulting in arginine deficiency in T cells and subsequent immune dysfunction. Supplementation with L-arginine can significantly improve the metabolic adaptability and survival of CD4⁺ and CD8⁺ T cells, thereby enhancing anti-tumor immune responses and inhibiting the growth of breast cancer [ 162 ]. Current cancer therapies largely focus on arginine deprivation. Notably, the impact of this strategy extends beyond tumor cells, as immune cell function is likewise highly dependent on arginine. Therefore, systemic arginine deprivation may concurrently impair effector T-cell function, thereby potentially weakening antitumor immunity [ 163 ]. However, such metabolic interventions can differentially affect immune cell subsets, with evidence suggesting that arginine deprivation may preferentially suppress the activity of immunosuppressive MDSCs [ 164 ].

Based on these findings, a promising therapeutic strategy has emerged: selectively increasing the supply of arginine to immune cells while simultaneously blocking its uptake by tumor cells. Arginine metabolism is modulated by arginine metabolic enzymes, and several arginine metabolic enzyme-related therapeutic approaches have been demonstrated to have favorable anti-tumor effects. Among these enzymes, protein arginine methyltransferases (PRMTs) and arginase have been extensively studied, and their regulatory mechanisms offer valuable insights for the novel anti-cancer therapies.

PRMT

PRMTs can catalyze arginine methylation and are mainly divided into three types: Type I enzymes (PRMT1, 2, 3, 4, 6, and 8), type II enzymes (PRMT5 and 9), and type III enzymes (PRMT7). PRMTs are often overexpressed in tumors and play an indispensable role in regulating cancer development and resistance [ 165 , 166 ]. For instance, PRMT3 can enhance glycolysis, thereby promoting HCC growth [ 167 ]. Moreover, studies have found that overexpressed PRMT5 can promote the cycle progression of cancer cells and form a positive feedback loop with PI3K-AKT signaling to enhance cell proliferation [ 168 ].

Studies have shown that the downregulation or knockout of PRMTs can enhance cancer cell senescence and decrease malignant biological behaviors [ 169 , 170 ]. In recent years, PRMTs inhibitors have shown significant anti-cancer effects. For example, PRMT5 inhibitors effectively decrease cancer drug resistance and suppress tumor growth when combined with AKT inhibitors or traditional chemotherapy drugs [ 168 , 171 ]. Moreover, type Ⅰ PRMT inhibitors can reduce the expression of the immunosuppressive cytokine VEGF in cancer cells, then increasing CD4 + and CD8 + T cell infiltration and the treatment efficacy of anti-PD-1 [ 172 ]. Currently, multiple clinical studies have confirmed that PRMT5 inhibitors, including JNJ-64,619,178, GSK3326595, and PF-06939999, exhibit significant anti-tumor activity and good prognostic effects against various cancers ( NCT04676516 , NCT03614728 , and NCT03854227 ). These findings suggest that the combination of PRMT inhibitors with conventional anti-cancer therapies may offer novel strategies for tumor treatment.

Arginase

Arginase is a key metabolic enzyme that can hydrolyze arginine to urea and ornithine and is classified into ARG1 and arginase 2 (ARG2). Both isoforms participate in arginine metabolism and share similar functions. Meanwhile, ARG1 is predominantly localized in the cytoplasm, whereas ARG2 is primarily found in mitochondria. Studies found that arginase is highly expressed in many cancers, including gastric, breast, liver, and colorectal cancers [ 173 , 174 ]. Arginase promotes tumor growth, metastasis, and metabolic adaptation by directly regulating L-arginine metabolism in cancer cells [ 175 ]. On the other hand, arginase is also crucial for immune function. In cancers, highly overexpressed arginase is classically associated with an immunosuppressive phenotype by depleting arginine and inhibiting T cell proliferation, activation, and cytotoxicity, leading to impaired immune function, cancer development, and immune evasion [ 176 – 178 ]. Some studies discovered that small extracellular vesicles containing ARG1 suppress the proliferation of CD4 + and CD8 + T cells and promote ovarian carcinoma growth [ 179 ]. Conversely, targeting ARG1 to normalize arginine metabolism can improve T cell exhaustion through the mTOR-T-bet axis, resulting in enhanced CD8 + T cell expansion [ 180 ]. Further studies have revealed that ARG1 inhibition not only optimizes arginine metabolic pathways but also reshapes the immunosuppressive microenvironment to ameliorate T cell exhaustion and increase the infiltration of CD8 + T cells, ultimately delaying tumor formation [ 176 , 180 , 181 ].

Given the dual roles of arginase in tumors, current therapeutic strategies are primarily divided into two approaches: arginase supplementation and arginase inhibition. The former is represented by pegylated recombinant human arginase, such as PEG-BCT-100, which has been engineered for improved stability and extended half-life. Clinical trials have demonstrated that the addition of PEG-BCT-100 to oxaliplatin-based chemotherapy has synergistic anti-tumor efficacy ( NCT02089633 ) [ 182 ]. Notably, when combined with autophagy inhibitors, these enzyme-based agents can synergistically kill cancer cells while reducing immune-related side effects [ 108 , 173 ]. On the other hand, arginase inhibition therapies rely heavily on intact T cell function, as no significant tumor suppression is observed in immunodeficient mouse models [ 183 ]. For example, arginase inhibitor CB-1158 improves anti-tumor immune responses by increasing CD8⁺ T cell infiltration and enhancing the efficacy of anti-PD-1 therapy [ 176 ]. A Phase I/II study evaluating CB-1158 in combination with immune checkpoint inhibitors in patients with advanced/metastatic solid tumors is currently underway ( NCT02903914 ) [ 184 ]. Similarly, OATD-02 has demonstrated the ability to reverse arginase-mediated immunosuppression effectively, owing to its prolonged target residence time [ 174 ].

In summary, the core challenge of arginase-targeted therapy lies in balancing the competitive utilization of arginine between tumor and immune cells. Reducing the impact of arginine deficiency in the immune system while inhibiting tumor arginine utilization.

Serine and Glycine

Serine and glycine are biosynthetically linked. They can be converted into each other through multiple enzymes. They together provide the necessary precursors for protein, nucleic acids, and lipids that are all crucial for cancer cell growth [ 24 ]. Cancer cells are dependent on serine and glycine, and often upregulate the de novo SSP to meet the demand for [ 185 , 186 ] serine. Moreover, excessive serine production within tumors has been reported to suppress the immunostimulatory activity of macrophages, contributing to the formation of an immunosuppressive TME. On the condition of serine/glycine deficiency, Cancer cells selectively take up exogenous serine and enhance the synthesis of serine through transcription factors and metabolic enzymes to maintain tumor proliferation [ 187 – 189 ]. When limiting serine/glycine levels, cytotoxic deoxysphingolipids accumulate in the blood circulation, delaying the tumor growth process [ 190 ]. Notably, the availability of serine and glycine are equally essential for the proliferation and function of immune cells. Serine metabolism critically regulates immune cell functional plasticity and phenotypic polarization. In particular, serine is indispensable for T cell activation and effector expansion by supplying glycine and one-carbon units required for nucleotide biosynthesis [ 191 ]. However, effector T cells possess a limited capacity for de novo SSP and therefore rely primarily on exogenous serine [ 191 ]. Increased serine uptake by tumor cells reduces serine availability for T cells, thereby impairing their proliferation and anti-tumor activity. Limiting the availability of serine and glycine to tumor cells, or inhibiting serine biosynthesis, can enhance antitumor immunity by increasing the availability of serine to T cells, restoring the function and cytotoxicity of T cells [ 192 – 194 ]. Therefore, these findings suggest that the strategies to limit the availability of serine and glycine can serve as potential therapies for cancer.

Recently, growing evidence has shown a close relationship between key serine/glycine metabolic enzymes and tumor progression, metastasis, and resistance to therapies. Multiple key serine/glycine metabolic enzymes are overexpressed in cancers to drive the tumor progression and metastasis, such as SHMT2, which drives the progression and metastasis of CRC by inhibiting β-catenin degradation [ 195 ]. Herein, we discussed metabolic enzymes of serine/glycine, including PHGDH, SHMT, and glycine decarboxylase (GLDC), which participate in the most important part of serine and glycine synthesis and function. The latest advances in these pathways can provide new insight for drug development, dietary interventions, and biomarkers for cancer.

PHGDH

PHGDH is an important enzyme involved in the de novo SSP and is aberrantly overexpressed in tumors. It promotes tumor progression through various mechanisms, such as by up-regulating oncogenic genes that drive malignant transformation, and consuming massive amounts of glucose in the serine and glycine de novo synthesis [ 196 , 197 ]. Inhibition of PHGDH by knocking out or silencing the PHGDH gene has been shown to significantly suppress tumor growth. Mechanistically, PHGDH inhibition decreases serine levels, AKT activity, and tight junction-related protein expression of cancer cells, significantly inhibiting tumor growth and prolonging survival in pancreatic cancer [ 196 ]. In addition to its metabolic functions, recent studies have uncovered the immunomodulatory role of PHGDH. Tumor-associated macrophages (TAMs) recruitment and differentiation are key parts of tumor growth and malignancy [ 198 ]. PHGDH can mediate de novo SSP of macrophages, and modulate TAMs and immunosuppressive macrophage polarization and proliferation via α-KG and mTORC1 signaling. PHGDH inhibition not only results in reduced TAM infiltration and a restrained immunosuppressive phenotype but also leads to the inhibition of tumor growth and partial restoration of anti-tumor immunity [ 199 ]. Additionally, PHGDH inhibition can alleviate the glycolysis and excessive proliferation of tumor endothelial cells, increase the CD8 + T population and ferroptosis, and improve T cell infiltration in tumors [ 193 , 200 ].

Given PHGDH’s central role in tumor metabolism, several PHGDH inhibitors have been developed and exhibit promising anti-tumor activity. For example, the PHGDH inhibitor NCT-502 can promote ferroptosis and inhibit bladder cancer progression [ 200 ]. CBR-5884, another inhibitor of PHGDH, inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating the ROS/Wnt/β-catenin pathway [ 201 ]. Notably, combination strategies involving PHGDH inhibitors and other anti-cancer agents show synergistic therapeutic effects. For instance, co-administration of CBR-5884 with PARP inhibitors olaparib, enhances treatment efficacy [ 201 ]. Additionally, PHGDH inhibitor NCT-503 in combination with pyruvate kinase M2 (PKM2) inhibitor exhibits remarkable anti-cancer effects by inducing the arrest and apoptosis of G2/M cell cycle [ 202 ]. Additionally, PHGDH deficiency reduced PD-L1 production in TAMs and partially restored anti-tumor T cell immunity, and increased the sensitivity of GBM to CAR-T therapy [ 193 , 199 ]. Therefore, future therapeutic strategies can focus on integrating PHGDH inhibition with ICB or adoptive cell therapy to achieve synergistic anti-tumor effects.

In conclusion, PHGDH can promote tumor progression by multiple pathways. PHGDH inhibitors can disrupt the metabolic processes of tumor cells and exert anti-tumor effects. Future studies could focus on elucidating the specific mechanisms by which PHGDH regulates immune responses within the TME, thereby developing more effective combination therapeutic strategies.

SHMT

SHMT can catalyze the reversible conversion between serine and glycine and is divided into two isoforms: SHMT1 and SHMT2, both of which are key players in cancer metabolic reprogramming. Both isozymes can catalyze the reversible conversion of serine to glycine. SHMT2 mainly catabolizes serine into glycine, while SHMT1 mainly produces serine from glycine in the cytosol [ 34 ].

Studies have demonstrated that SHMT2 is significantly upregulated in cancers such as lung cancer, ovarian cancer, and breast cancer [ 203 , 204 ]. In CRC, SHMT2 promotes tumor proliferation and metastasis by stabilizing β-catenin and preventing its ubiquitylation-mediated degradation [ 195 ]. Moreover, in high-risk neuroblastoma, SHMT2 increases expression of N-Myc via phosphorylation and activation of Akt-2, leading to increased cellular proliferation, colony formation, and metastasis [ 205 ]. Knocking out SHMT2 can significantly inhibit the growth of gastric cancer, Burkitt lymphoma and CRC [ 195 , 206 , 207 ]. Mechanistically, SHMT2 inhibition significantly reduces intracellular glycine levels, which inhibits the mTOR pathway and thereby triggers autophagic degradation of the oncogenic transcription factor TCF3 [ 207 ].

As for SHMT1, previous studies have indicated that SHMT1 is necessary for various cancer growth, such as lung cancer, colon cancer, and ovarian cancer. In ovarian cancer, SHMT1 can promote tumor growth and progression by regulating levels of N-acetylneuraminic acid, which in turn enhances the expression of pro-oncogenic inflammatory cytokines IL-8 and IL-6 [ 208 ]. In lung cancer, SHMT1 knockdown can induce cytoplasmic serine starvation, then limiting the migratory ability of the cancer cells [ 203 ].

Many studies have demonstrated that SHMT1/2 suppression increases cellular sensitivity to oxidative stress and inhibits tumor progression [ 209 – 211 ]. Further, the SHMT inhibitor enhances the in vivo therapeutic efficacy of paclitaxel in tumors. SHIN2, a dual SHMT1/2 inhibitor, can be used in combination with methotrexate, especially for methotrexate resistant cells, providing a new treatment for ALL [ 210 , 212 ]. Therefore, targeting SHMT1/2 is an attractive target to inhibit tumor growth and reduce chemotherapy resistance.

GLDC

GLDC, which can decompose glycine into a single carbon, is one of the core metabolic enzymes involved in regulating glycine metabolism. Numerous studies have found that GLDC exhibits complex functions and tissue-specific functions across various cancers. GLDC is hyperactive in some cancers, such as prostate and breast cancer, and is associated with tumor occurrence, migration, and immune escape, finally leading to poor survival [ 213 – 215 ]. Specifically, high levels of GLDC can maintain mitochondrial protein lipoylation and change glycolysis, glycine/serine metabolism, and pyrimidine metabolism, thus promoting cell malignant transformation and tumor growth [ 215 – 217 ]. Notably, inhibition of GLDC activity via acetylation or silencing the GLDC gene can suppress glycine metabolism and tumor proliferation, eventually delaying tumor progression [ 216 , 218 , 219 ].

Nevertheless, other studies found that the expression of GLDC is lower in highly malignant HCC and renal cell cancer (RCC). Downregulation of GLDC decreases ROS-mediated ubiquitination of cofilin to enhance HCC progression and intrahepatic metastasis, whereas GLDC overexpression can increase the autophagy of tumor cells and inhibit invasion of HCC and RCC cells [ 220 – 222 ]. The above two opposite results suggest that exploring the role and mechanism of GLDC in different cancers is a premise for utilizing GLDC as an anti-cancer target.

Dietary therapy of amino acids

The progression of malignant tumors is dependent on the uptake and metabolism of amino acids. Interestingly, in addition to excessive intake and synthesis of amino acids in vivo, cancers also depend on exogenous sources of amino acids for optimal growth [ 223 ]. The level of amino acids obtained from the diet greatly affects the metabolism of amino acids in vivo, establishing a link between nutrition and tumor cell metabolism [ 224 ].

In recent decades, dietary amino acid interventions have emerged as a promising strategy in cancer treatment. By precisely modulating the intake of specific amino acids, it is possible to selectively restrict nutrient availability to tumor cells, reshape metabolic competition within the TME, and thereby enhance anti-tumor efficacy (Fig. 4 ) [ 225 ]. Compared with conventional therapies, such dietary interventions offer notable advantages, including reversibility, low toxicity, and compatibility with existing treatment modalities, highlighting their significant potential for clinical translation [ 226 ]. The following sections will explore the molecular mechanisms and therapeutic prospects of amino acid restriction or supplementation strategies in cancer treatment.

Methionine

Dietary restriction of methionine

Methionine is a sulfur-containing EAA obtained solely through dietary sources that plays a critical role in cancer cell growth. Cancer cells exhibit an increased demand for methionine, while deprivation and blockade of methionine can significantly impact cancer outcomes by promoting ferroptosis, lipid peroxidation, DNA damage, and cellular senescence [ 225 , 227 ]. Similar to certain amino acids, methionine is also vital for anti-tumor immunity, adequate methionine is essential for the function and survival of immune cells [ 228 ]. However, tumor cells upregulate methionine transporter SLC43A2 to outcompete immune cells for methionine within the TME [ 229 ]. The high methionine consumption by cancer cells limits methionine availability to immune cells, particularly T cells. Restricting methionine uptake has been shown to increase tumor-infiltrating CD8⁺ T cells, thereby suppressing tumor growth and enhancing anti-tumor immunity [ 230 ]. Conversely, methionine supplementation for immune cells can relieve the methionine competition pressure of immune cells and restore AMPK expression, therefore lowering PD-1 levels [ 231 ]. Consequently, targeting methionine metabolism presents a potential new strategy for cancer treatment and enhancing immunity. However, given the critical role of methionine metabolism in the interplay between immune and tumor cells, systemic MR inevitably impacts immune cell function. In particular, methionine depletion may contribute to the formation of an immunosuppressive TME, ultimately compromising therapeutic efficacy [ 232 ]. Notably, methionine supplementation can restore T cell immunity and reduce T cell apoptosis in cancer patients [ 229 ]. Therefore, selectively targeting methionine metabolism in either tumor cells or immune cells can be optimized to enhance the efficacy of cancer therapy by disrupting tumor methionine metabolism while preserving antitumor immune responses.

At present, the MR diet has emerged as an appealing therapeutic approach as a less toxic alternative to traditional cancer treatments. Studies have shown that MR diet can affect methionine level, sulfur metabolism, nucleotide metabolism, one-carbon metabolism, and DNA methylation, depending on S-adenosylmethionine (SAM) in various tumors, then significantly increasing tumor cell death and delaying the multiple tumors progression and metastasis rate [ 233 – 235 ]. Additionally, in esophageal squamous cell carcinoma, dietary restriction of methionine and cystine inhibits ESCC proliferation and induces apoptosis of cancer cells via decreasing GSH and downregulating the expression of SLC43A2 [ 236 ]. In terms of therapy combination, MR diet can synergize with other one-carbon metabolic therapies, PD-1 blockade, 5-fluorouracil, and radiotherapy [ 237 ]. Furthermore, methionine is required for some immune cells to maintain proliferation and activation. Tumor cells often outcompete T cells for methionine to reduce T cell function [ 229 ]. MR diet can also increase CD8 + T cell infiltration and cytotoxicity within tumors, and the intermittent rather than continuous MR diet accelerates tumor cell ferroptosis and sensitizes CD8 + T cells-mediated cytotoxicity [ 230 , 238 ].

However, a recent study has found that intestinal microorganisms can affect the anti-tumor immune efficacy of the MR diet. Mechanistically, in intestinal tumors, dietary MR disrupts immune response by reducing the gut microbiota and hydrogen sulfide (H 2 S) production, which is crucial for immune cell survival [ 232 ]. This finding revealed an unexpected negative interaction in MR, sulfur deficiency, and anti-tumor immunity.

Most of the above views suggest that MR can inhibit tumor progression, but this effect is not absolute. The function of dietary MR is contextually dependent on the relative requirement for methionine by tumor and immune cells. Moreover, the effect of dietary methionine on tumor growth and immunity is also related to non-cell-autonomous activation of immune cells mediated by gut microbiota. Therefore, the possible anti-cancer benefits of the MR diet should require careful consideration of the microbiota and the immune system.

Serine/Glycine

Dietary restriction of serine/glycine

Current studies have confirmed that various tumor cells exhibit a dependence on exogenous serine and glycine [ 30 ]. Dietary serine/glycine restriction can effectively reduce circulating serine/glycine levels, thereby impairing the antioxidant defense mechanisms of tumor cells. This metabolic disruption delays tumor progression and prolongs survival [ 195 ]. Additionally, dietary serine/glycine restriction induces excessive accumulation of toxic deoxysphingolipids within tumors, further inhibiting tumor growth [ 187 ]. Moreover, Tong et al. found that the serine/glycine-free diet promotes the accumulation of cytotoxic CD8 + T cells and diminishes immune-suppressive cells to enhance anti-tumor immunity and inhibit CRC growth [ 189 ].

Dietary serine/glycine restriction can also be combined with other anti-cancer therapies [ 206 ]. For instance, dietary serine/glycine restriction can sensitize cancer cells to radiation therapy [ 28 ]. Moreover, dietary serine/glycine restriction combined with the PHGDH inhibitor PH755 strongly inhibits tumor growth due to damaging overall protein synthesis and one-carbon availability, augmenting the therapeutic efficacy of dietary serine/glycine restriction alone [ 223 ]. Notably, dietary serine/glycine restriction also shows promising clinical efficacy when combined with immunotherapy, and has been proven safe and feasible in a phase I trial (ChiCTR2300067929) [ 192 ].

In summary, dietary restriction of serine and glycine exerts multifaceted anti-tumor effects. It not only directly inhibits tumor growth through metabolic intervention but also enhances therapeutic outcomes by modulating systemic immune responses. Existing evidence suggests that this approach is safe, compatible with other therapeutic modalities, and represents a novel avenue for the treatment of solid tumors.

Arginine

Dietary restriction of arginine

Early studies have demonstrated that arginine-deficient diets slow down CRC, HCC, and prostate cancer growth, significantly decrease some tumor incidence, and promote tumor regression [ 239 – 241 ]. Dietary arginine restriction can affect tumor growth by reducing arginine availability and polyamine metabolism [ 239 ]. Mechanistically, dietary arginine restriction induces mitochondrial distress, metabolic reprogramming, tumor DNA damage, and chromatin leakage of cancer cells, as well as promotes cytotoxicity by aspartate exhaustion, resulting in tumor cell death [ 241 , 242 ]. On the other hand, arginine restriction also shows synergistic therapeutic potential. For example, in glioblastoma, it enhances radiosensitivity [ 243 ]. Additionally, it also increases tumor cell susceptibility to GCN2 inhibitor and SLC inhibitors by effectively reducing arginine uptake within the TME [ 244 ]. At present, phase I/II single-arm clinical studies are gradually being conducted to evaluate the safety and efficacy of dietary restriction of arginine in clinical cancer treatment ( NCT07038044 , NCT00578721 ).

Dietary supplementation of arginine

Most studies have demonstrated that dietary restriction of arginine exhibits high therapeutic efficacy in tumor treatment. Interestingly, recent evidence also indicates that dietary supplementation of arginine can exert anti-tumor effects, primarily by enhancing anti-tumor immunity [ 162 , 245 ]. Specifically, dietary supplementation of L-arginine increases the percentage of CD8 + cytotoxic T lymphocytes in cancer, enhances immunogenic tumor immunity, and strengthens innate and adaptive immune responses, thus prolonging the patient’s survival time [ 246 ]. Furthermore, dietary supplementation of L-arginine can enhance natural cytotoxicity in peripheral blood lymphocytes and has a synergistic effect with anti-PD-L1 therapy [ 247 , 248 ].

Collectively, these findings suggest that dietary modulation of arginine exerts beneficial effects in cancer therapy. However, the impact of dietary supplementation of arginine depends on the specific metabolic characteristics and immune microenvironment of individual tumors. For instance, in tumors such as pancreatic cancer, the microenvironment is often dominated by ARG1-expressing MDSCs, which deplete L-arginine and thereby suppress T-cell-mediated immunity [ 249 ]. L-arginine deprivation promotes MDSC S accumulation and further inhibits anti-tumor T-cell responses [ 250 ]. Whereas dietary supplementation of arginine significantly reduces MDSC frequency and ROS levels, restoring immune function and suppressing tumor progression [ 246 ]. Thus, the inhibitory effect of dietary supplementation of arginine on immunogenic tumor growth is largely attributed to its immunostimulatory role, particularly enhancing the cytotoxic activities of macrophages, natural killer cells, and T cells [ 251 , 252 ].

In summary, various cell types may respond differently to altered arginine availability and changes in immune reactivity within the TME. However, whether dietary supplementation or deprivation of arginine is more beneficial for cancer patients remains unclear. This uncertainty arises because sufficient arginine levels are essential for normal immune function and cancer surveillance, yet arginine is also required for tumor cell growth. Therefore, the net therapeutic outcome of arginine modulation may vary, underscoring the need to consider the complex interactions between the immune system and the TME, as well as to tailor arginine-based interventions according to each patient’s tumor genotype and immune profile [ 162 ].

Cysteine/Cystine

Dietary restriction of cysteine/cystine

Cysteine is a sulfur-containing NEAA involved in catalysis, detoxification, metal transport, and oxidative stress within cells. Notably, cysteine and its oxidized form, cystine, play an important role in maintaining cellular redox homeostasis. Both cysteine and cystine provide energy for tumor cells and mediate tumor growth by various signaling and cellular processes [ 253 ]. Mechanistically, Badgley et al. found that PDAC cells utilize cysteine to synthesize GSH and coenzyme A, thereby suppressing ferroptosis [ 254 ]. Wu et al. revealed that cystine can promote cancer cell growth in vitro and immunodeficient mice, predominantly by inhibiting SESN2 transcription through the GCN2-ATF4 axis, leading to mTORC1 activation. In addition, cystine confers resistance to irinotecan chemotherapy and oxaliplatin by synthesizing GSH [ 255 ]. More importantly, a recent study found that tumor cells can outcompete T cells for the uptake of cystine, resulting in T cell exhaustion and death. Reduced cystine uptake of tumor cells decreases T cell ferroptosis and restores anti-tumor immunity [ 254 ].

Multiple studies have demonstrated that dietary cystine/cysteine restriction represents a promising anti-cancer strategy. Dietary cystine restriction significantly reduced cystine/cysteine levels and inhibited tumor growth in mice without weight loss, and enhanced the anti-tumor effects of oxaliplatin with good safety [ 255 ]. Mechanistically, recent studies have indicated that dietary cystine and methionine deprivation make glioma cells more sensitive to ferroptosis [ 225 ]. These studies suggest that dietary cystine/cysteine restriction could be an option for cancer treatment. Nevertheless, this intervention strategy faces significant challenges. In addition to transporter-mediated uptake, cellular cysteine can be synthesized from other amino acids, such as methionine, by the transsulfuration pathway [ 256 ]. Liu et al. have shown that endogenous transsulfuration-mediated cysteine production can support cell growth under extracellular cysteine restriction, so dietary restriction efficacy may be reduced [ 257 ]. Therefore, when developing cysteine/cystine-restricted anti-cancer therapies, it is essential to take the compensatory activation of the transsulfuration pathway into account as a potential mechanism of resistance.

Glutamine

Dietary supplementation of glutamine

Glutamine is a major dietary amino acid. Glutamine-enriched diets may replete host glutamine stores and can significantly inhibit the growth of several cancers [ 258 ]. Mechanistically, dietary glutamine supplementation effectively increases the glutamine concentration and its downstream metabolite, α-KG, in tumors, then drives H3K4me3 hypomethylation, and then suppresses epigenetically-activated oncogenic pathways in melanoma [ 258 ]. Additionally, previous studies have found that dietary glutamine significantly improves T-lymphocyte responsiveness [ 259 ]. Recently, Cao et al. revealed that high dietary glutamine significantly increased glutamine concentration in TME to suppress Treg differentiation, subsequently increasing the infiltration of CD8 + T cells [ 139 ]. These findings further demonstrate that dietary glutamine can inhibit cancer by enhancing immunity. Furthermore, dietary glutamine supplementation can reduce ulcers and cardiotoxicity caused by cancer treatment and accelerate mucosal healing, inhibit the occurrence of cachexia, and protect normal tissues from chemotherapy and radiation damage [ 260 , 261 ]. Therefore, the above evidence suggests that dietary glutamine supplementation can serve as a potential intervention to inhibit tumor growth.

Nano-systems for modulating amino acids metabolism

Beyond dietary interventions, the rapid development of nanomedicine has provided an innovative strategy for modulating amino acid metabolism in cancer therapy. In practical applications, traditional amino acid-based therapies, such as enzyme inhibitors, amino acid analogs, and metabolic enzymes, have faced several pharmacological challenges. These include unfavorable pharmacokinetics (PK), low tumor-specific accumulation, and dose-limiting systemic toxicity. The latter is often attributed to non-selective amino acid depletion or inhibition in healthy tissues [ 247 ]. Nanomedicine-based delivery systems have emerged to overcome these limitations and enable precise intervention in tumor metabolic processes. By encapsulating amino acid-targeting agents, nanocarriers can enhance drug solubility, prolong plasma half-life, and facilitate selective drug delivery to tumor sites via passive or active targeting mechanisms, thereby maximizing therapeutic efficacy, while minimizing adverse effects on normal tissues [ 262 , 263 ]. Moreover, nanotechnology allows for the co-delivery of multiple therapeutics, synergizing with other therapies, and simultaneously disrupting complementary metabolic pathways to overcome compensatory mechanisms and prevent drug resistance [ 264 , 265 ]. Beyond merely improving drug delivery, the intrinsic interactions between nanocarriers and amino acid metabolism represent an emerging area of investigation. Certain nanomaterial designs can directly influence nutrient availability or the metabolic state within the TME, potentially producing synergistic effects with their amino acid-targeting payloads [ 266 ]. This section summarizes various nanotechnology-based amino acid therapies and their applications in enhancing antitumor immunity (Table 3 ; Fig. 5 ).

Metallic and magnetic nanomaterials

Metal nanomaterials have been widely studied in medical imaging and drug delivery because of their unique optical, magnetic, and photothermal features. Additionally, some metal ions released from metal nanomaterials can participate in cancer and immune processes, playing a crucial role in several key anti-cancer activities. Among these, metal-organic frameworks (MOFs) are porous nanomaterials built by connecting metal ions or clusters with organic ligands. Notably, the high surface area and large pore size of MOFs enhance their ability to load encapsulated drugs, giving MOFs significant potential for cancer drug delivery [ 180 , 267 ]. MOFs can be activated by specific endogenous or exogenous stimuli and release their cargo only under the selected conditions.

Direct delivery of amino acids

As mentioned earlier, the methionine dependence of tumors can be used for cancer treatment, but methionine is difficult to enter TME due to its highly aqueous solubility [ 268 ]. Therefore, a series of nanoplatforms has been designed to increase methionine levels in TME and reduce methionine levels in tumor cells. Zheng et al. developed an approach to label assembly of hydrophilic methionine into NPs (MPC@Fe) to relieve methionine metabolic stress in the TME. MPC@Fe can persistently accumulate in the tumor for a long time due to tumor-selective aggregation in acidic TME, and overcome the limited loading capacity and rapid diffusion of methionine. During this aggregation process, methionine could be sustained released. Notably, it significantly induces the CD8 + T cells infiltration into TME through stimulating immunogenic cell death, effectively improving the survival and activation of CD8 + T cells, decreasing 50 ~ 60% apoptosis of CD8 + T cells, and remarkably promoting tumor regression [ 268 ].

In addition to methionine, arginine is an essential metabolite for tumors and is a precursor of nitric oxide (NO). NO is crucial for gas therapy (GT), which has received much attention for cancer treatment. NO can directly kill tumor cells by damaging DNA at high concentrations, and also can react with ROS to produce highly cytotoxic reactive nitrogen species (RNS) [ 269 , 270 ]. Arginine can spontaneously react with hydrogen peroxide (H 2 O 2 ) in the TME to generate NO for GT [ 271 ]. The metallic and magnetic nanomaterials loaded with arginine, including HA@MOF/D-arginine and Fe 3 O 4 @PLGA/LA NPs. They could readily accumulate at the tumor site via the enhanced permeability and retention (EPR) effect [ 266 , 271 , 272 ]. Both nano-systems can produce more NO through arginine delivery, effectively improve the hypoxic environment in cells, and enhance tumor cell toxicity, destroying redox homeostasis to inhibit tumor proliferation [ 266 , 271 ]. Notably, when the NPs accumulate within tumors, certain cationic NPs, such as iron-based NPs, can react with H 2 O 2 through the Fenton reaction to increase ROS [ 273 , 274 ]. This is an effect inherently induced by the NPs themselves. Furthermore, iron-produced ROS can further react with NO to generate peroxynitrite anions and other RNS, which exert synergistic antitumor effects when combined with arginine-loaded NPs [ 275 ].

In addition, the incorporation of hyaluronic acid (HA) into HA@MOF/D-arginine facilitates its specific binding to cancer cells, enhances the radiosensitivity of osteosarcoma, and effectively prevents tumor recurrence, demonstrating both safety and efficacy [ 266 ].

Moreover, a multifunctional nano-vaccine (BMT@LA) was developed, black mesoporous titanium dioxide (BMT) loaded with L-arginine, and it can selectively enrich at the tumor site through the EPR effect. BMT@LA exhibits a sono-response property, upon ultrasound (US) irradiation, BMT@LA can simultaneously trigger BMT and L-arginine to produce 1 O 2 and NO, respectively. Finally, it effectively inhibits primary tumors and induces immune reactions. When BMT@LA is combined with an anti-PD-L1 immune checkpoint inhibitor, it exhibits a robust anti-tumor immune response, effectively eliminating primary tumors and suppressing metastasis [ 276 ].

These multifunctional nanomaterials not only deliver amino acids but also incorporate additional functional components that synergistically enhance anti-cancer efficacy, resulting in potent tumor growth inhibition.

Delivery of regulators of amino acid metabolic pathways

Apart from the direct delivery of amino acids, many amino acid-related drugs have also been designed to enhance efficacy, improve targeting, and reduce side effects through nanoplatforms. For example, Ying et al. constructed a MOF nanoplatform called PMZH, which can target the tumor methionine transporter SLC43A2 by delivering CRISPR plasmids, thereby affecting methionine metabolism in T cells and tumor cells. PMZH can stabilize in physiological conditions but degrade in acidic TME, ensuring complete release within the tumor. PMZH reduces side effects, promotes systemic immune response, and effectively inhibits tumor recurrence and metastasis [ 267 ]. Additionally, the nutrient metal ions as delivery materials in PMZH can induce ROS production, thereby stimulating the activation of the cGAS/STING pathway and promoting CD8 + T cell infiltration [ 277 ]. Wang et al. designed a sequentially positioned MOF nano transformer (M 199 BM), which can target the same type of tumor site by endowing its surface with a cancer cell membrane. M 199 BM effectively killed cancer cells and selectively exhausted methionine pools in tumors by inhibiting methionine salvage pathways [ 278 ]. Besides, both of the above MOFs can restrict the methionine utilization of tumors and strengthen cancer immunotherapy by restoring T cell function.

Furthermore, many studies show that inhibition of glutamine metabolism can inhibit tumor growth. Du et al. designed a MOF nano-system called PCP-MOF@G@B for effective loading of glucose oxidase (GOD) and BPTES (drug inhibitors that inhibit glycolysis and glutamine metabolism). The PCP-MOF@G@B excitingly improves tumor penetration and cellular uptake efficiency via integrating the pH-responsive size reduction, and shows exciting performance in tumor penetration and induces mitochondrial damage and cell cycle arrest, thereby achieving a significant cancer-killing effect [ 265 ]. Additionally, inhibiting tumor uptake of glutamine by blocking amino acid transporters represents a prospective and effective strategy for suppressing tumor growth [ 279 ]. Zhou et al. developed MOF NPs αMM@PLTs to deliver α-methyl-DL-tryptophan (α-MT, a transporter SLC6A14 blockade drug), favoring US/GSH-responsive combinational therapeutics between glutamine deprivation and SDT [ 280 ]. αMM@PLT targets tumor sites through the inherent TME tropism of platelet (PLT) cells, US stimulates the MOF to generate ROS, releasing NPs, specifically blocking the amino acid transporter SLC6A14 of cancer cells and stimulating glutamine starvation [ 280 ].

The above two nano-systems disrupt the energy supply of the tumor, further inhibiting tumor growth with negligible side effects and excellent biocompatibility.

Lipid nanovesicle

Lipid nanovesicles can serve as drug carriers for cancer treatment due to their ability to transport therapeutic agents. They have wide applications in biomedical fields, including diagnosis, drug delivery, and immune therapy [ 281 ].

Direct delivery of amino acids

Photodynamic therapy (PDT) exhibits unique characteristics, including low systemic toxicity and local treatment by topical light irradiation. Under light irradiation, PDT could lead to necrosis or apoptosis through the generation of highly cytotoxic ROS by photosensitizers [ 282 ]. Both IA-PEP and PIDA nanovesicle systems incorporated the PS PEGylated indocyanine green (mPEG-ICG) and effectively encapsulated L-arginine, demonstrating excellent targeted delivery capability through the EPR effect. IA-PEP and PIDA generate ROS and react with L-arginine under laser irradiation, significantly increasing the NO concentration in tumors and effectively triggering GT [ 264 , 283 ]. Notably, these two systems have other characteristics. Specifically, PIDA achieves a quadruple synergistic therapy of chemotherapy, photothermal therapy, PDT, and GP, efficiently reversing multidrug resistance and inhibiting tumor growth, demonstrating safe and significant anti-tumor effects [ 283 ]. Meanwhile, IA-PEP functions as a three-way synergistic treatment system including NO therapy, PDT, and mild photothermal therapy, which possesses substantial tumor elimination and synergistic therapeutic effect [ 264 ].

Delivery of regulators of amino acid metabolic pathways

Zhang J designed a multivesicular liposome L-arg@MVLs, which is slowly released in acidic TME. L-arg@MVLs continuously supply L-arginine to immune cells in TME, and selectively achieve L-arginine starvation in tumor tissues by using short hairpin RNA to knock down the tumor arginine transporter CAT-2 expression. This approach promotes the infiltration and activation of CD8 + T cells within the tumor, thereby enhancing the efficacy of immunotherapy and demonstrating a potent tumor-clearing effect when combined with anti-PD-1 antibodies [ 284 ]. This study provides critical design principles for developing nanoplatforms capable of simultaneously overcoming tumor drug resistance and potentiating anti-tumor immunity.

Polymeric NPs

Polymeric NPs are defined as micro-molecules with submicron sizes ranging from 10 −1,000 nm. Polymeric NPs facilitate the sustained release of drugs at targeted cancer sites. Compared to conventional pharmaceutical formulations, polymeric NPs exhibit strong stability, high drug-loading capacity, and low toxicity [ 262 ].

Direct delivery of amino acids

An injectable nanomedicine, PLGA@ICG@l-Arg/Gel, is a multifunctional platform that combines PDT and GP. The PLGA@ICG@l-Arg/Gel system exhibits thermosensitive behavior, undergoing a rapid sol-to-gel transition upon injection in vivo, which facilitates its localization and retention at the tumor site, thereby enabling sustained drug release. Under near-infrared (NIR) irradiation, PLGA@ICG@l-Arg would generate ROS to oxidize L-arginine to produce NO, which synergistically kills cancer cells. Moreover, ROS would further react with NO to induce the generation of RNS, which enabled the activation of matrix metalloproteinases (MMPs) in TME. Activated MMPs were able to degrade the high-density collagens, deconstructing the tumor extracellular matrix. A significantly higher anti-tumor effect was achieved by the treatment of PLGA@ICG@l-Arg/Gel with enhanced collagen depletion [ 282 ]. This system utilizes PDT-induced ROS cascade generation and NO therapy to provide an efficient strategy for synergistic cancer treatment.

Delivery of regulators of amino acid metabolic pathways

Kynurenine, a metabolite of tryptophan, plays a significant role in inducing immunosuppression within TME through multiple pathways, making it a promising target for cancer therapy. Wang et al. constructed a supramolecular hydrogel encapsulating the drugs kynureninase and doxorubicin (DOX). Upon injection into the peritumoral region, it rapidly forms a stable gel under physiological conditions and enables the rapid release of DOX and kynureninase within TME, which can enhance tumor immunogenicity and continuously consume kynurenine. This local therapy has potential benefits in preventing tumor recurrence, boosting anti-tumor immunity, and inhibiting tumor growth [ 285 ].

Likewise, nanovesicles Az-NaCMCS and ADI@MiSuNv encapsulated the ADI, which catalyzes the decomposition of arginine. Both have good permeability and can be enriched in tumors, ensuring the activity and stability of ADI while significantly reducing the arginine availability in tumors, and strongly inhibiting the growth of liver cancer cells MH134 and Hep3B [ 286 , 287 ]. ADI@MiSuNv can promote cancer cell cycle arrest, autophagy, and apoptosis [ 287 ]. Taken together, these strategies highlight the importance of targeting metabolic pathways in the TME to enhance cancer treatment and improve patient outcomes.

Conclusion

During the high-proliferation phase of tumorigenesis, cancer cells undergo metabolic reprogramming that significantly alters glucose, lipid, and amino acids metabolism pathways. Notably, the metabolic reprogramming of amino acids not only significantly influences the proliferation of cancer cells but also impacts anti-tumor immunity through modulation of the survival and function of immune cells. It highlights the multifaceted effects of amino acids metabolism on cancer cells and immune cells in the TME (Fig. 6 ). The therapeutic potential of targeting aberrant amino acid metabolism has been recently evaluated to enhance anti-cancer immunity. Compared to monotherapy (anti-PD-1 or chemotherapy), combination therapy with either amino acid supplementation or metabolic enzyme inhibitors enhances efficacy. Therefore, targeting amino acids metabolism is a feasible and promising cancer therapy that can both inhibit tumor growth and enhance anti-tumor immunity. However, amino acid deprivation can reprogram immune cell metabolism through competition with cancer cells, thereby shaping anti-tumor immunity [ 288 , 289 ]. Therefore, targeting amino acids metabolism profound effects on the tumor immune microenvironment must be carefully considered.

As described above, targeting metabolic enzymes of amino acids is a promising therapeutic strategy. Currently, several preparations or inhibitors targeting metabolic enzymes of amino acids have advanced to clinical trials. Nevertheless, many challenges remain to be addressed. On the one hand, the metabolic plasticity of tumor cells poses a significant barrier to the efficacy of targeted therapies [ 290 ]. Tumor cells can adapt to changes in amino acid levels by increasing the uptake of alternative amino acids or by activating compensatory energy metabolism pathways [ 291 ]. For example, in pancreatic cancer, inhibition of GLS triggers acute cellular adaptations to glutamine limitation. These include the activation of stress response pathways such as endoplasmic reticulum stress and antioxidant responses, along with extensive metabolic rewiring. Cancer cells enhance fatty acid oxidation as an alternative source of energy and biosynthetic precursors [ 290 ]. Furthermore, cancer cells up-regulate multiple other enzymes to sustain glutamine metabolism, targeting a single amino acid metabolic enzyme often fails to achieve complete tumor suppression [ 292 , 293 ]. This metabolic plasticity allows cancer cells to survive initial therapeutic pressure. While treatment may eliminate the majority of amino acid-dependent cells, rapidly adapted cancer cells utilizing these compensatory pathways gain a growth advantage, ultimately leading to tumor regrowth and disease progression. This adaptability enables tumor cells to develop resistance to targeted therapies, thereby limiting their clinical utility [ 294 ]. To overcome the above limitations, rational combination therapies employing multiple metabolic inhibitors may enhance anti-tumor efficacy by simultaneously disrupting compensatory pathways [ 292 ]. Additionally, GLS1 inhibitors have been reported to suppress the growth of platinum-resistant colorectal and ovarian cancer cells [ 294 , 295 ]. These findings suggest that, in clinical trials, drugs targeting amino acid metabolism may be most effective when used in combination with conventional anticancer therapies such as chemotherapy, radiotherapy, and immunotherapy, underscoring their clinical relevance. At present, combinations of amino acid-related therapies with standard therapeutic approaches have been extensively explored (Table 4 ). Moreover, the ICB targeting immune checkpoint proteins and adoptive cell transfer based on tumor-infiltrating lymphocytes or CAR T cells are frontline cancer immunotherapies. Consequently, growing research efforts have focused on integrating amino acid restriction with existing therapeutic modalities to potentiate anti-tumor responses and improve therapeutic outcomes. On the other hand, tumors exhibit marked heterogeneity in their reliance on specific amino acids. This heterogeneity is driven by genetic factors, metabolic reprogramming, and the unique characteristics of the TME. As a result, most metabolic inhibitors are likely to benefit only specific cancer subtypes. However, this heterogeneity also presents an opportunity for precision medicine. By leveraging the differences in amino acids metabolism dependence, we can design precise therapies tailored to specific cancer subtypes. For instance, Myc-driven cancers, such as small-cell lung cancer and triple-negative breast cancer, have demonstrated pronounced glutamine addiction. In these cancers, the GLS inhibitor CB-839 has been shown to significantly inhibit tumor cell proliferation [ 296 ]. Similarly, KRAS mutant CRCs exhibit a critical dependence on serine and glycine, and pharmacologic restriction of these amino acids, such as using PHGDH inhibitors, can significantly impair tumor growth [ 297 ].

Secondly, numerous studies have demonstrated that dietary intervention with amino acids can serve as a potential strategy for cancer therapy. The primary goals of dietary interventions are to enhance therapeutic efficacy, alleviate treatment-related toxicity, and improve patients’ quality of life, functioning mainly as an adjunctive nutritional strategy. Nevertheless, several challenges remain in clinical application. For example, the effect of dietary interventions varies considerably among individuals, influenced by multiple factors including host genetic background, gut microbiota composition, and overall metabolic status [ 298 , 299 ]. Therefore, the potential risks of dietary amino acid interventions must be carefully assessed. Excessive restriction or supplementation of certain amino acids may disrupt nutritional balance. Conversely, supplementation of specific amino acids may accelerate tumor progression by promoting anabolic metabolism in malignant cells. Appropriate dietary interventions have been shown to partially reverse cancer-associated cachexia in advanced patients, stimulate muscle protein synthesis, and improve physical performance [ 300 – 302 ]. To address this complexity, future studies should focus on identifying predictive biomarkers to optimize patient stratification. For instance, the expression of specific metabolic enzymes in tumors may indicate sensitivity to amino acid restriction, while circulating metabolite profiles and microbiome characteristics hold promise as dynamic biomarkers for monitoring the efficacy of nutritional interventions [ 256 , 303 ].

Moreover, dietary modifications do not uniformly affect nutrient levels across different tissues or within the TME. Distinct cancer types exhibit differences in metabolic activity, energy substrate preference, and nutrient dependency, and these differences further influence the efficacy of dietary therapy [ 304 ]. In nutrient-rich organs, dietary restriction alone may be insufficient to reduce key metabolites to levels that impair tumor growth, whereas tumors arising in nutrient-poor organs or regions may be more responsive. Similarly, the outcomes of combining diet with chemotherapy drugs can differ substantially. Although amino acid-based interventions may synergize with chemotherapy, radiotherapy, or immunotherapy to enhance anti-cancer efficacy, the specific combination regimen must be tailored to cancer type, anatomical site, and stage, and implemented under stringent clinical supervision and careful monitoring. Moreover, most current studies on dietary therapy are limited to supplementing or restricting a single amino acid, while investigations into the combined modulation of multiple amino acids remain limited. Therefore, further studies should focus on elucidating the mechanism by which dietary modifications suppress cancer in vivo, and attempt to investigate the effect of combined dietary intervention of multiple amino acids.

Additionally, with the rapid development of nanotechnology, more and more nano-systems are being developed to deliver amino acids and amino acid-related drugs to alter amino acid levels within cancer cells or TME, and have initially demonstrated certain anti-cancer efficacy. Moreover, the nano-systems can selectively regulate the amino acid levels of specific immune cells within the TME, avoiding immune dysfunction caused by amino acid deprivation in tumor cells. However, several challenges still exist for the clinical translation of nanomaterial-based therapeutics. Firstly, the main consideration of nanomaterials is biosafety. Multi-component nanomaterials often result in complex metabolism, biodegradation, and excretion behaviors. For example, metal nanomaterials may induce oxidative stress and cell toxicity in vivo by promoting the generation of ROS and the release of metal ions [ 305 – 307 ]. Therefore, a long-term systematic evaluation on the biocompatibility and biodegradability of nanomaterials is highly valuable. Secondly, in different types of tumors, it is necessary to consider the transport and degradation of NPs in the immunosuppressive mechanism of TME. Especially, to ensure biological safety and reduce the potential toxicity of NPs, the appropriate administration routes should be selected [ 305 ]. Additionally, it is worth mentioning that recent studies found that the combination of nanomaterials and engineered bacteria shows great promise to inhibit tumor growth [ 308 ]. The in vivo manipulation of engineered bacteria is vitally beneficial in tumor therapy with numerous natural advantages, such as specific colonization ability, and genetic engineering can modify bacteria to express anti-tumor drugs [ 309 ]. Therefore, many therapeutic NPs have been combined with bacteria to fabricate biohybrids to achieve better anti-tumor effects [ 310 ]. Notably, several engineered bacteria have been developed and exerted the anti-tumor effect mediated by amino acids [ 247 ]. Therefore, in the future, the combined therapeutic strategies of engineered microbial therapies and nano-systems can be explored to regulate amino acid levels, thereby achieving more efficient and precise cancer treatment.

Despite the significant challenges that currently exist in targeting amino acids metabolism to treat cancer, the expected progress in studies and technological advancements suggests that this field is poised to yield novel breakthroughs in tumor therapeutics. Future studies should focus on understanding the complex regulatory networks governing amino acids metabolism within tumor cells. Concurrently, developing more precise targeted therapies with improved efficacy and safety, and their rational combination with chemotherapy, immunotherapy, and radiotherapy, represents a critical therapeutic direction. In actual clinical practice, effective and personalized treatment plans should be formulated according to the unique characteristics of different malignancies and individual patient parameters.

Acknowledgements

Not applicable.

Abbreviations

3-phosphoglycerate

arginine deaminase

acute lymphoblastic leukemia

AMP-activated protein kinase

arginase 1

arginase 2

arginine-succinate synthase 1

asparagine synthetase

black mesoporous titanium dioxide

colorectal cancer

doxorubicin

essential amino acid

enhanced permeability and retention

Food and Drug Administration

general control nonderepressible 2

glycine decarboxylase

glutaminase

glucose oxidase

glutamine synthetase

glutathione

gas therapy

hydrogen peroxide

hydrogen sulfide

hyaluronic acid

hepatocellular carcinoma

immune checkpoint blockade

myeloid-derived suppressor cells

monomethylarginine

matrix metalloproteinases

PEGylated indocyanine green

metal-organic frameworks

methionine restriction

mechanistic target of rapamycin complex 1

nicotinamide adenine dinucleotide phosphate

non-essential amino acid

near-infrared

nitric oxide

nanoparticles

oxaloacetate

oxidative phosphorylation

programmed cell death protein 1

pancreatic ductal adenocarcinoma

programmed cell death ligand 1

phosphoglycerate dehydrogenase

pharmacokinetics

pyruvate kinase M2

polylactic acid glycolic acid

platelet

protein arginine methyltransferases

phosphoserine aminotransferase 1

phosphoserine phosphatase

renal cell cancer

reactive nitrogen species

reactive oxygen species

recommended phase 2 dose

S-adenosylmethionine

serine hydroxymethyltransferase

serine synthesis pathway

tumor-associated macrophages

tricarboxylic acid

tumor microenvironment

ultrasound

V-domain Ig suppressor of T cell activation

α-ketoglutarate

α-methyl-DL-tryptophan

Authors’ contributions

RSQ and ZXY wrote the manuscript. WZ and YKF critically reviewed and edited the manuscript. All authors contributed to the article, and read and approved the submitted version.

Funding

This work was supported by grants from the Natural Science Foundation of China (82472700, 82472745, 82472365, 82373400, 82372660, 82272685, 82202260 and 82173248), the Project funded by China Postdoctoral Science Foundation (2022TQ0221), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD22006), Scientific and Technological Innovation Ability Enhancement Project for Junior Faculties of Sichuan University (2024SCUQJTX043), the Sichuan University postdoctoral interdisciplinary Innovation Fund (10822041A2103).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All subjects have written informed consent.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

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

Shiqi Ren, Xinyi Zhou and Zhen Wang contributed equally to this work.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.