Dietary methionine restriction in cancer development and antitumor immunity

Abstract

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

Keywords: antitumor immunity; gut microbiota; methylation; redox homeostasis; sulfur metabolism.

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

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.

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

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.

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

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.

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.

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.