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Published in final edited form as: Trends Endocrinol Metab. 2024 Feb 20;35(5):400–412. doi: 10.1016/j.tem.2024.01.009

Dietary methionine restriction on cancer development and antitumor immunity

Ming Ji 1,2, Qing Xu 1,2, Xiaoling Li 1,*
PMCID: PMC11096033  NIHMSID: NIHMS1961485  PMID: 38383161

Abstract

Methionine restriction has been shown to suppress tumor growth and improve the responses to various anti-cancer therapies. However, methionine itself is required for proliferation, activation, and differentiation of T cells that are critical for antitumor immunity. The dual impact of methionine, influencing both tumor and immune cells, has generated concerns regarding the potential consequences of methionine restriction on T-cell immunity and its possible role in promoting cancer. In this review, we systemically examined current literature on the interactions between dietary methionine, cancer cells, and immune cells. Based on recent findings in immunocompetent animals with methionine restriction, we further discussed how tumor stage-specific methionine dependence of immune cells and cancer cells in the tumor microenvironment could ultimately dictate the response of tumors to methionine restriction.

Keywords: sulfur metabolism, methylation, redox homeostasis, antitumor immunity, gut microbiota

Interactions between dietary methionine, cancer cells, immune cells, and gut microbiota

Cancer cells demand abundant nutrients for their rapid growth, epigenetic manipulation, and redox balance [1]. Restricting nutrients like glucose and amino acids, especially methionine (see Glossary), has been explored as a less toxic alternative to traditional cancer treatments [2-4]. As the only sulfur-containing essential amino acid, methionine initiates protein translation and fuels vital biological processes such as methylation and redox homeostasis [5], which are closely linked to cancer development and tumor progression. The discovery of cancer methionine dependency has opened the avenue to exploiting methionine restriction (MR) as a promising nutritional strategy in cancer therapy [5-7], complementing its established benefits in aging and metabolic health [8,9].

The importance of methionine in fundamental cellular processes makes sustained methionine supply also essential for the proliferation and activation of immune cells. As an integral part of antitumor immunity, immune cells like T cells, Natural killer cells and tumor associated macrophages are responsible for identifying and eliminating abnormal cancerous growth [10]. Recent studies have shown that T cells require methionine for their activation and differentiation [11-13]. Since methionine is an essential amino acid that can only be obtained from the diet, competition between cancer cells and immune cells for dietary methionine has presented a challenge for effective cancer treatment with MR.

Another key player in dietary methionine intervention-based cancer therapy is the human microbiome, whose composition and function are significantly influenced by different diets [14]. In turn, the microbiota and its metabolites could also modulate host metabolism and immune system [15,16]. Therefore, MR as a dietary approach involves complex interactions between diets, cancer cells, immune cells, and microbiota. Consequently, despite promising findings that MR inhibits tumor growth and improves cancer therapy, factors such as the timing, duration, and degree of MR, the stage and the type of cancer, as well as the immune status of patients, could all confound the tumor response to MR-based treatments [17-20]. This review will focus on recent research on the precise mechanisms and clinical implications of these interactions.

Methionine metabolism

Methionine metabolism is regulated through several interconnected pathways (Figure 1). In the methionine cycle, methionine transforms into the universal methyl donor S-Adenosyl methionine (SAM). SAM is also crucial for polyamine synthesis, producing byproducts that can regenerate methionine via the methionine salvage pathway. SAM can be converted to homocysteine (Hcy), which, through remethylation (via the folate cycle) or transsulfuration pathways, contributes to the synthesis of methionine, cysteine, and other key sulfur-containing molecules such as hydrogen sulfide (H2S) and glutathione (GSH). These pathways, integral to one-carbon metabolism, sustain the synthesis of purine and pyrimidine (the folate cycle), methylation (the methionine cycle), and redox balance (the transsulfuration pathway), all of which are vital for cell growth and function [5].

Figure 1. One-carbon metabolic pathways and key enzymes.

Figure 1.

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MAT1A: Methionine Adenosyltransferase 1A; MAT2A and 2B: Methionine Adenosyltransferase 2A and 2B; BHMT: Betaine-Homocysteine S-Methyltransferase; CBS: Cystathionine Beta-Synthase; CTH: Cystathionine Gamma-Lyase; CDO1: Cysteine Dioxygenase Type 1.

Cell-autonomous impact of methionine metabolism on tumor growth

The reliance of cancer cells on methionine was initially revealed when tumor cells were found to be more dependent on exogenous methionine than normal cells [7]. Although the degree of methionine dependence varies among human cancer cells [21], this finding led to a hypothesis that limiting methionine intake could cell-autonomously hinder cancer growth. Indeed, various studies have demonstrated that MR inhibits tumor growth and enhances the effectiveness of cytotoxic agents in both cultured cells and animal models [19,22-26]. Cancer cell-autonomous mechanisms, such as cell cycle arrest, apoptosis, and alterations in nucleotide and redox metabolism, have been reported to underlie the antitumor effect of MR [5]. In-depth metabolic analyses further revealed that MR directly impacts metabolic flux in one-carbon metabolism in tumor cells, leading to inhibition of tumor growth and sensitization of tumors to chemotherapy and radiotherapy [5,26]. In this section, we summarize some key cell-autonomous mechanisms linking MR-induced metabolic changes to phenotypic outcomes in cancer cells (Figure 2).

Figure 2. Cell-autonomous impact of methionine metabolism on cancer cells.

Figure 2.

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Cancer cells are highly dependent on exogenous methionine for their proliferation, survival, and stress resistance. Firstly, SAM-dependent methylation of DNA and histones epigenetically regulates the expression of key factors involved in mitophagy, apoptosis, and oncogenesis, thereby inhibiting cell death and promoting tumorigenesis. SAM-dependent methylation of RNA and non-histone proteins involved in regulation of immune inhibition and type I interferon response in cancer cells hinders their response to immunotherapy. Secondly, sulfur-containing antioxidative molecules derived through the transsulfuration pathway, including cysteine, GSH, and H2S, are important for cancer cells survival and stress resistance. GSH protects cancer cells from ferroptosis and apoptosis induced by ROS and lipid peroxides. It also promotes oxidative phosphorylation (OXPHOS) and ATP production through glutathionylation (GS) of mitochondrial enzymes. H2S, when at a low physiological concentration, acts as a cytoprotective agent by suppressing ROS, promoting energy metabolism, and enhancing angiogenesis. Many of these actions are mediated, at least partially, by protein sulfhydration (SH). Consequently, MR, cysteine restriction, and/or elevated polyamine flux have been reported to inhibit tumor growth, induce cell death, and sensitize tumor to different anti-cancer therapies. Figure was created with BioRender.com.

SAM-dependent methylation

As the primary methyl donor for the methylation of DNA, histone, RNA, and other proteins, SAM is important for epigenetic regulation of gene expression, DNA repair, and protein functions [27,28]. MR has been reported to increase cancer cell death through suppression of SAM-dependent DNA methylation. For instance, in gastric cancer cells, the promoter of a mitochondrial mitophagy receptor protein BNIP3 is hypermethylated. MR induces demethylation of this promoter, enhancing BNIP3 expression and promoting mitophagic cell death [29].

MR and subsequent SAM depletion also induce rapid change of histone methylation [30], which alters gene expression and may mediate the effect of MR on cancer [31]. For example, in acute myeloid leukemia, methionine starvation reduces H3K36me3 and induces cell death [32]. In tumor-initiating cancer cells (TIC), MR causes drastic decrease of both SAM levels and overall histone methylation, disrupting the tumorigenic potential of TIC [33]

MR also affects RNA methylation, which takes place mainly at the N6 position of an adenine base (m6A) [34]. MR has been shown to reduce the m6A methylation thereby affecting the translation of immune checkpoint transcripts PD-L1 and V-domain Ig suppressor of T cell activation (VISTA) in tumor cells, enhancing their response to antitumor immunity [35].

Additionally, MR can suppress tumor growth through reduced methylation of non-histone proteins. CyclicGMP-AMPsynthase (cGAS), a cytosolic DNA sensor that produces cGAMP to activate STING mediated type I interferon signaling upon binding of cytosolic DNA, has been shown to be methylated by methyltransferase SUV39H1 in cancer cells [36]. This modification leads to chromatin sequestration of cGAS. MR reduces the methylation of cGAS, decreasing its chromatin tethering and promoting its DNA binding, which in turn activates the type I interferon pathway in cultured cancer cells. Interestingly, targeting the SUV39H1-cGAS axis in either cancer cells or host cells increases immune cell infiltration, reduces tumor growth, and sensitizes tumors to radiotherapy and immunotherapy [36].

SAM-dependent polyamine biosynthesis

SAM is important for synthesis of polyamines. Elevated polyamine flux can compete with other methionine/SAM-dependent pathways for SAM in cancer cells, making them sensitive to interventions that block methionine recycling or disrupt redox balance. For example, enhanced polyamine flux synergizes with inhibition of methionine salvage pathway to induce apoptosis in prostate cancer cells [37]. Increased polyamine pathway activity also makes cancer cells more dependent on de novo-synthesized cysteine from methionine, thereby synergizing with cysteine starvation to induce their death [38]. Therefore, therapeutic interventions that deplete methionine/SAM through activating the polyamine pathway have the potential to enhance the efficacy of MR-mediated cancer treatment.

Cysteine, GSH, and redox homeostasis

Cysteine obtained from diet or synthesized from methionine through the transsulfuration pathway is rate-limiting for synthesis of GSH, an important thiol-containing antioxidant that maintains redox homeostasis and protects cells from oxidative stress induced by reactive oxidative species (ROS) and lipid peroxides [39,40]. Due to their increased ROS production, many cancer cells have high levels of GSH, which contributes to their resistance to anticancer therapy [41]. MR-induced GSH depletion sensitizes cancer cells to anticancer therapy. For instance, in triple-negative breast cancer (TNBC) cells, MR-induced GSH depletion leads to increased accumulation of ROS, which activates NRF2 to induce thioredoxin reductase (TXNRD), rendering tumors more dependent on the thioredoxin pathway for redox balance. Consequently, MR synergizes with TXNRD inhibitor auranofin to inhibit TNBC tumor growth [42].

Depletion of cysteine or cystine, which is often removed in the MR diets in animal studies, mimics the impact of MR on GSH and antioxidative defense in cancer cells. In leukemia stem cells (LSCs), cysteine depletion impairs GSH synthesis and reduces glutathionylation of succinate dehydrogenase A (SDHA), a key regulator of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation inhibits ETC II activity and oxidative phosphorylation, diminishing ATP production and inducing LSC death [43]. In multiple cancer allograft/xenograft models, systemic depletion of cysteine or cystine with an engineered human cyst(e)inase diminishes GSH, resulting in cell cycle arrest and death in cancer cells [44].

Cysteine depletion-induced GSH reduction can also trigger ferroptosis. For example, cysteine depletion through inhibition of cystine import induces ferroptosis in pancreatic cancer [45]. In glycolytic ovarian clear cell carcinoma, cysteine depletion suppresses tumor growth primarily by oxidative stress-dependent necrosis and ferroptosis [46]. In esophageal squamous cell carcinoma, dietary methionine/cystine restriction downregulates the expression of methionine transporter SLC43A2, GPX4a, and the NFκB signaling pathway. The blocked NFκB pathway further decreases the expression of SLC43A2 and GPX4, inducing ferroptosis and apoptosis [47]. In glioma, methionine/cysteine deprivation can synergize with the GPX4 inhibitor RSL3 to increase lipid peroxidation and ferroptotic cell death [48]. Interestingly, a recent report showed that cyst(e)ine deprivation-induced shortage of lysosomal cystine, but not cytosolic cysteine, sensitizes cancer cells to ferroptosis through the aryl hydrocarbon receptor-ATF4 axis [49].

Cysteine depletion may play a large role in MR-mediated antitumor effects, as cysteine supplementation reverses the effects of MR on adiposity and ROS production [50,51] as well as on tumor inhibition [20]. In line with this notion, the cystine deprivation-induced defect in antioxidative defense in cancer cells can be affected by the manipulation of upstream methionine metabolism. Short-term methionine starvation prompts transcription of cation transport regulator homolog 1 (CHAC1), a protein essential for GSH degradation, enhancing tumor ferroptosis [18]. Intermittent methionine deprivation also induces tumor ferroptosis, synergizing with PD-1 blockade-activated CD8+ T cells to improve the tumor response to immunotherapy. However, prolonged methionine deprivation suppresses ferroptosis initiation by impeding the translation of CHAC1 [18]. Conversely, activation of transsulfuration pathway that generates cysteine and GSH attenuates ferroptosis induced by cysteine deprivation [52,53].

H2S

The transsulfuration pathway also generates H2S, a gasotransmitter that regulates vasodilation, cellular bioenergetics, and anti-inflammation. H2S also modulates cell signaling through protein sulfhydration [54,55]. The role of H2S in cancer appears to be complex with a bimodal pharmacological character [54]. Generally, H2S maintains normal physiology and acts as a cytoprotective and antioxidant agent at a low physiological concentration. These actions affect the proliferation and migration of cancer cells in a tumor-cell-type dependent manner. After reaching a certain threshold, H2S may promote tumorigenesis. On the other hand, at a higher concentration, H2S exhibits tumor inhibition effects through various mechanisms, including mitochondrial inhibition, activation of cell death signaling, intracellular acidification, and activation of apoptosis. Consequently, H2S donors have been considered as anti-cancer drugs [54,56].

Enzymes involved in metabolism of sulfur-containing amino acids (SAAs)

Given the significant impact of methionine and sulfur metabolic irregularities on tumor development, it is not surprising that SAA metabolic enzymes are frequently dysregulated in cancers [57-59]. For instance, in human liver tumors, many SAA enzymes are downregulated. This reduction correlates with aggressive tumors and a poor prognosis [60-63]. Recently, we discovered that HNF4α, the master regulator of hepatic genes, transcriptionally regulates key enzymes in SAA metabolism in the liver transsulfuration pathway, such as BHMT, CBS, CTH, CDO1, and the liver-specific MAT1A that converts methionine into SAM. This regulation dictates the sensitivity of liver cancer to MR-induced cell death. Knocking down HNF4α or SAA enzymes in HNF4α-positive epithelial liver cancer lines impairs SAA metabolism and promotes epithelial-mesenchymal transition, increasing resistance to MR [19].

Several studies have targeted MAT2A, the rate-limiting enzyme that produces SAM from methionine in extrahepatic tissues, for MR-mediated cancer treatment [64-66]. In breast cancer stem cells (CSC), the combination of MR and MAT2A inhibition is more effective than either alone for tumor inhibition [64]. In diffuse midline gliomas, low levels of MAT2A increase their dependence on methionine. MR therefore reduces the tumor growth and extends the survival of tumor-bearing mice [65]. MAT2A is upregulated in cisplatin resistant bladder cancer cells, and its knockdown synergizes with MR to restore cisplatin sensitivity in immunodeficient mice but not in an immunocompetent model. Instead, inhibition of SLC7A6, a methionine transporter that is highly expressed in cisplatin resistant cancer cells but minimally expressed in CD8+ T cells, is additionally required for MAT2A inhibition to overcome cisplatin resistance in immunocompetent mice [66].

Non-cell-autonomous impact of methionine metabolism on cancer through antitumor immunity

Methionine is also critical for the growth and survival of non-cancer cells. For instance, a sustained supply of exogenous methionine is required for the proliferation and activation of T cells [13], a critical component of antitumor immunity [11]. Therefore, methionine metabolism could also non-cell-autonomously impact cancer growth and progression through regulation of immune cell-mediated antitumor immunity. Below are a few mechanisms underscoring these non-cell-autonomous impacts (Figure 3).

Figure 3. The impact of methionine metabolism on immune cells and antitumor immunity.

Figure 3.

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First, methionine (Met) is critical for the proliferation and activation of effector T cells, a vital component of antitumor immunity. SAM-dependent methylation of H3K79me2 increases the expression STAT5 thereby activating CD8+ T cells. This modification also increases the expression of AMPK in conventional CD4+ T cells, leading to suppression of PD1. During tumor progression, tumor cells can outcompete T cells for methionine in the tumor microenvironment by increasing the expression of SLC43A2, impairing T cell-mediated antitumor immunity. Moreover, the methionine uptake of tumor-infiltrating T cells can be inhibited by the acidic metabolic waste products within the tumor microenvironment, which reduces H3K27me3 at the promoters of critical T cell memory genes, keeping them in a 'stem-like memory' state with reduced effector functions. Furthermore, dietary methionine and cysteine (Cys) are important precursors for gut microbial production of H2S, which can enhance T cell survival and activity by increasing GAPDH sulhydration and glycolysis. MR can therefore impair effector T cell-mediated antitumor immunity. Finally, methionine and sulfur metabolites are also important for the survival and function of regulatory immune cells in vitro. SLC43A2-mediated methionine uptake is essential for the survival of activated Treg cells, and H2S-mediated sulfhydration of NFYB promotes the differentiation of Treg through TETs and FOXP3. System Xc- mediated import of cystine in MDSCs sequesters extracellular cysteine and cystine to block full T cell activation. Figure was created with BioRender.com.

SAM-dependent histone methylation in regulation of T cell immunity

Methionine can boost T cell activation and differentiation via SAM-mediated enhancement of histone activation marks. In CD4+ helper T cells, MR decreases H3K4me3 on the promoters of genes involved in cytokine production and cell cycle progression, suppressing pathogenic Th17 cell expansion and mitigating T cell-mediated neuroinflammation and autoimmune diseases in mice [67]. Bian et al. recently showed that tumor cells can surpass CD8+ T cells in the competition for methionine via high expression of SLC43A2 in the tumor microenvironment. This competition decreases intracellular methionine and SAM in T cells, leading to reduced H3K79me2 on the promoter of STAT5, a key player in T cell development, and hindering T cell-mediated antitumor immunity [12]. Reduced methionine in the tumor microenvironment also affects CD4+ helper T cells. Low methionine in CD4+ T cells decreased H3K79me2, leading to downregulation of AMPK. Reduced AMPK then increases the expression of PD-1, the T cell checkpoint inhibitor, and impairs antitumor immunity of CD4+ T cells [68].

The methionine uptake of tumor-infiltrating T cells could also be inhibited by the acidic metabolic waste products within the tumor microenvironment [69]. This metabolic rewiring reduces intracellular SAM and the deposition of H3K27me3, a repressive histone mark, at the promoters of critical T cell memory-associated genes, such as CCR7, KLF2, LEF1, and TCF7. T cells maintained in an acidic environment, therefore, are kept in a 'stem-like memory' state with inhibited effector functions. Intriguingly, when adoptively transferred into recipient mice, these T cells display a long-term in vivo persistence and antitumor activity [69].

H2S, gut microbiota, and immune system

Sulfur-containing metabolites produced in the transsulfuration pathway, including GSH and H2S, can also modulate the function and activity of immune cells involved in innate and adaptive immunity [70,71]. For instance, GSH is required for T-cell proliferation and effector functions [72]. H2S-mediated immune regulation, like what is observed in cancer cells, is context- and dose-dependent (bell-shaped or bimodal), with an optimal H2S “zone” for physiological functions and therapeutic improvements of various immune cells in health and disease. Mechanistically, an optimal H2S level protects immune cells from ROS-induced toxicity, increases their viability, and stimulates their mobility, thereby enhancing their function [70]. Additionally, physiological levels of H2S enhance activation of T cells by promoting cell proliferation and the expression of markers characteristic of the activation state [73]. Therefore, H2S could regulate cancer development and progression non-cell-autonomously through modulation of antitumor immunity.

Interestingly, the gut is a major H2S-producing organ, with a large portion of H2S produced from sulfate-producing gut microbiota that metabolize inorganic or organic sulfur compounds in the diet [74]. Given that gut microbiota is known to interact with diets to regulate host metabolism and immune system, and that the modulation of gut microbiota can enhance immunotherapy for cancer [15,16,75], H2S could be an important mediator of MR on cancer development and treatment. Indeed, a recent study from our group has found that MR reduces H2S produced from the microbiota, and this reduction contributes at least partially to MR-induced impairment of antitumor immunity [20]. Mechanistically, H2S enhances immune cell survival and activity by increasing GAPDH sulhydration, boosting glycolysis.

Methionine metabolism in regulatory immune cells

Methionine and sulfur metabolites are also important for the survival and function of regulatory immune cells. Activated T-regulatory (Treg) cells) have high methionine uptake via SLC43A2, which is essential for their survival upon IL-2 deprivation in vitro [76]. Moreover, the differentiation of Treg cells can be driven by H2S-mediated sulfhydration of NFYB, which promotes the expression of methylcytosine dioxygenases Tet1 and Tet2, leading to demethylation of the promoter of Foxp3 [77]. Myeloid-derived suppressor cells (MDSCs), known for their strong inhibition of T-cell-mediated antitumor immunity, express the system xc- transporter that imports cystine but lacks the cysteine export transporter [78]. This expression pattern allows MDSCs to import extracellular cystine without releasing cysteine back into their microenvironment, leading to sequestration of extracellular cysteine and cystine that blocks full T cell activation in vitro [78].

The impact of tumor methionine metabolism on T cell immunity

Dysregulated methionine metabolism in tumor cells has been linked to impaired T cell immunity. For instance, in hepatocellular carcinoma (HCC), elevated SAM and 5-methylthioadenosine (MTA), two key metabolites in the methionine salvage pathway, induce T cell exhaustion [79]. As discussed previously, increased methionine uptake of tumor cells during tumor progression via SLC43A2 can outcompete CD8+ T cells for methionine, leading to impaired T cell survival and function [12]; SAM-mediated m6A methylation of PD-L1 and VISTA in tumor cells inhibits T cell immunity [35]; and SAM-mediated methylation of cGAS reduces type I interferon signaling in cultured cancer cells, and reduced methylation of cGAS is linked to increased immune cell infiltration and sensitivity to immunotherapy in vivo [36]. These studies suggest that elevated methionine metabolism in tumor cells may blunt the response of tumors to antitumor immunotherapy.

The impact of MR on antitumor immunotherapy

The importance of methionine and its metabolites in the metabolic and epigenetic regulation of immune cells, particularly T cells, strongly suggests that MR could impair immune cell-mediated antitumor immunity. In support of this notion, intratumoral supplementation of methionine have been reported to increase CD8+ T cell immunity in tumor-bearing mice and patients with colon cancer [12] and reduce PD-1 expression in CD4+ T cells and suppress tumor growth [68]. Dietary supplementation of methionine, cystine, or a hydrogen sulfide donor stimulates anti-tumor immunity and suppresses tumor progression [20]. However, recent studies have revealed the dichotomy of MR on the response of tumors to antitumor immunotherapy in immunocompetent mice [18,20,35,80,81], highlighting the multifaceted effects of MR on the interaction between cancer cells and immune cells in the tumor microenvironment (Figure 4). Careful comparison of the experimental design and therapeutic outcome of each of above studies suggests that the impact of MR on the response of tumors to antitumor immunotherapy is likely dependent on the cancer stage. In studies where MR was initiated after tumors were established, MR synergizes with antitumor immunotherapy to suppress tumor growth [18,35,80,81]. However, in the study where MR was started before tumors were initiated/established, MR impairs the efficacy of antitumor immunotherapy [20].

Figure 4, Key Figure. The impact of MR on tumor growth and therapeutic response is dependent on the relative methionine dependence of T cells vs cancer cells in the tumor microenvironment.

Figure 4, Key Figure.

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MR is anti-cancer in immunodeficient individuals with tumors that are sensitive to MR. In healthy people or immunocompetent patients at early cancer stages, MR may become pro-cancer by impairing T cell activation, which could lead to uncontrolled tumor growth or resistance to immunotherapy. In cancer patients at advanced stages, tumor cells may exhibit a higher dependency on methionine in comparison to T cells. MR could synergize with non-immune-mediated therapeutic regimens to suppress tumor progression. Therefore, the impact of MR on tumor growth and therapeutic response is affected by the immune status and tumor stage. Figure was created with BioRender.com.

For established tumors in immunocompetent mice, MR enhances their response to antitumor immunotherapy through multiple mechanisms. These tumor-cell-autonomous actions include decreasing m6A RNA methylation on the transcripts of immune checkpoint genes PD-L1 and VISTA thereby reducing their expression and their inhibition of T cells [35], stimulating the transcription of a GSH degradation protein CHAC1 thereby sensitizing tumor cells to ferroptosis [18], or promoting cGAS-STING pathway and type I interferon signaling in cultured cancer cells in vitro [36,81]. In these studies, MR increased the response of established tumors to antitumor immunotherapy indirectly by either reducing the immune-inhibiting activity of tumor cells or increasing their sensitivity to redox stress. Therefore, with the exception of one study showing that MR skews innate tumor-associated macrophages toward a more tumoricidal M1-type phenotype [80], currently, there is a lack of direct evidence confirming that MR could genuinely augment the efficacy of immunotherapy by boosting immune cell function and their antitumor immunity in these experimental settings.

The experimental setting in which the dietary methionine intervention was started prior to the onset of tumor growth directly investigates the influence of dietary intervention on the intrinsic antitumor immunity derived from immune cells [20,82]. In this setting, dietary MR exacerbates cancer progression and impairs the outcome of antitumor immunotherapy in multiple cancer models in immunocompetent mice by diminishing the survival and activity of immune cells, notably T cells [20]. This finding aligns with prior studies showing that methionine metabolism is indispensable for the immune responses, especially T cell-mediated antitumor immunity [12,13,67,68]. Moreover, in addition to previously revealed SAM-mediated epigenetic regulation [12,67,68], dietary MR hinders the proliferation and activation of T cells primarily through impairment of redox homeostasis downstream of SAM, as supplementation of cysteine (a H2S precursor), a H2S donor, or H2S-producing microbes, counteracts the MR-induced resistance to anti-tumor immunotherapy [20]. Therefore, methionine and its downstream metabolites play crucial roles in regulating gene expression, redox balance, and cellular proliferation in T cells, ultimately impacting their ability to mount effective immune responses against cancer.

In conclusion, the complex relationship between dietary methionine intervention and antitumor immunity involves the direct modulation of immune cell function as well as indirect immune regulation from gut microbiota and cancer cells, and this relationship is sensitive to tumor stage. Thus, the timing of MR initiation and tumor stage will determine the MR-induced cancer outcomes.

Concluding remarks and future perspectives

Despite extensive research into the effects of MR on tumors, currently, there are no ongoing cancer clinical trials involving the combination of dietary methionine intervention and immunotherapy. However, a recent study in healthy adults indicates that outcomes of dietary sulfur amino acid restriction in animal models are applicable to humans [83]. As previously noted, methionine and its downstream products are important for overall functions of both tumor cells and immune cells. Thus, whether dietary MR exerts pro-cancer or anti-cancer effects is contextually dependent on the relative requirement for methionine by tumor cells compared to immune cells (Figure 4). Preclinical mouse studies suggest that MR might be advantageous for immunocompromised cancer patients due to its direct inhibitory effects on tumor growth without involvement of the immune system. On the other hand, for healthy people or immunocompetent patients at early cancer stages, MR may impair immune cell activation, which could lead to uncontrolled tumor growth or resistance to immunotherapy. In advanced cancer cases, tumor cells may exhibit a higher dependency on methionine in comparison to immune cells within the tumor microenvironment. At this stage, the synergistic integration of MR with non-immune-mediated therapeutic regimens, such as chemotherapy or radiation therapy, represents a promising therapeutic strategy (Figure 4, key figure).

Of important note, dietary MR exerts profound impacts on metabolism, immunity, and overall health [83]. For example, MR in young rats stunts growth and impairs bone health [84]. Several studies that examine the feasibility of MR treatment in humans have suggested that short-term MR treatment is well tolerated, but the long-term safety and potential side effects of sustained MR remain to be further understood [26,85-88]. Thorough research is therefore imperative to assess the safety of dietary methionine intervention for diverse patient populations. Importantly, substantial challenges persist before clinical implementation (see Outstanding questions). In the future, a multidisciplinary approach is needed to address these challenges and to further test the personalized and tumor stage-specific strategies for cancer treatment with methionine intervention.

Outstanding questions.

  1. Which tumor types are more sensitive to methionine intervention?

  2. Could biosensors/tracers evaluating tumor methionine dependence be developed to guide methionine intervention for cancer treatment?

  3. Which specific probiotic strains have the potential to amplify the therapeutic effects of methionine supplements or H2S donor?

  4. What is the impact of MR on immune cells other than the T-cells, such as B cells, natural killer cells, neutrophils, monocytes, and dendritic cells?

Highlights.

  1. As a sulfur-containing essential amino acid important for a broad array of fundamental cellular processes, methionine is critical for the proliferation, stress resistance, and overall functions of both cancer cells and immune cells.

  2. Dietary methionine regulates the antitumor immunity by directly influencing immune cell function and indirectly modulating the immune system through interactions with gut microbiota and cancer cells.

  3. The ultimate effect of dietary methionine restriction on tumor growth and therapeutic response depends on the relative reliance of T cells versus cancer cells on methionine in the tumor microenvironment.

  4. Any possible anti-cancer benefits of dietary methionine restriction require careful consideration of the immune system, microbiota, and tumor stage.

Acknowledgements

We thank members of the Li laboratory, and Drs. Lih-Wen Deng and Zefeng Wang for critical reading of the manuscript. The work related to this article was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205). We apologize to those colleagues whose work has not been cited due to space limitations.

Glossary

Antitumor immunity

refers to the body's immune responses against the development and progression of cancer. T cells play a central role in antitumor immunity. Cytotoxic (CD8+) T cells recognize and eliminate tumor cells. Helper (CD4+) T cells promote the response of cytotoxic T cells, while T-regulatory cells (Tregs) expressing the transcription factor FoxP3 suppress the activity of cytotoxic T cells. Myeloid-derived suppressor cells (MDSCs) are known to inhibit the activation of CD8+ and CD4+ T cells.

Ferroptosis

a form of cell death characterized by iron-dependent lipid peroxide accumulation, GSH is required to detoxify peroxides through glutathione peroxidase 4 (GPX4).

Methionine and cysteine

the only two sulfur-containing proteinogenic amino acids. Methionine is essential and is acquired solely through diet, while cysteine is semi-essential and can be obtained from diet or synthesized from methionine. Cystine is the more stable dimeric form of cysteine.

Oxidative stress

a condition caused by an imbalance in redox status, characterized by an excess of reactive oxygen species (ROS) or inadequate antioxidants that scavenge and neutralize ROS. This condition can cause damage to cellular components and contribute to the development of various diseases, including cancer.

PD-1/PD-L1 Targeting Immunotherapy

a type of cancer treatment that focuses on blocking the interaction between the programmed cell death protein 1 (PD-1) on T cells and its ligand, programmed death-ligand 1 (PD-L1) on cancer cells. This interaction is a key immune checkpoint that can suppress the immune response and allow cancer cells to evade elimination by the immune system. Antibody-based inhibitors of PD1/PDL1 disrupt the immune checkpoint pathway and boost T cell-mediated antitumor immunity, exhibiting substantial effectiveness against many tumors.

Polyamine synthesis

the cellular process that generates polyamines such as putrescine, spermidine, and spermine. Polyamines are small positively molecules that interact with negatively charged macromolecules, such as DNA, RNA, protein, and phospholipids, and are essential for cell growth and function.

Protein sulfhydration

a post-translational modification that adds a thiol group (-SH) to cysteine residues in proteins, forming a persulfide bond (-SSH).

Redox balance

the equilibrium between oxidation and reduction reactions that involve the transfer of electrons between molecules. Maintaining the balance between the oxidized and reduced molecules in the body is crucial for cellular function and overall health.

SAM-dependent methylation

a biochemical process in which a methyl group is transferred from SAM to various substrates including the cytosine base of DNA, the lysine (K) and arginine (R) residues of histone proteins, the N6 position of the adenine base (m6A) of RNA, the lysine (K) residue of non-histone proteins.

Thioredoxin reductase (TXNRD)

the rate-limiting enzyme in the thioredoxin pathway that reduces thioredoxin using NADPH. The thioredoxin system is a key antioxidant system in defense against oxidative stress by regulating protein dithiol/disulfide balance.

Footnotes

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Declaration of interests

The authors declare no competing interests.

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