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Frontiers of Medicine

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Front. Med.    2023, Vol. 17 Issue (4) : 585-616    https://doi.org/10.1007/s11684-023-1012-z
REVIEW
Immunometabolism: a new dimension in immunotherapy resistance
Chaoyue Xiao1, Wei Xiong2, Yiting Xu3, Ji’an Zou3, Yue Zeng1, Junqi Liu1, Yurong Peng1, Chunhong Hu1,4, Fang Wu1,4,5,6()
1. Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
2. NHC Key Laboratory of Carcinogenesis and Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha 410078, China
3. Xiangya School of Medicine, Central South University, Changsha 410013, China
4. Hunan Cancer Mega-Data Intelligent Application and Engineering Research Centre, Changsha 410011, China
5. Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, The Second Xiangya Hospital, Central South University, Changsha 410011, China
6. Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
Keywords immune cell      immunometabolism      metabolic reprogramming      immunotherapy      resistance      tumor microenvironment      immune checkpoint inhibitor     
Corresponding Author(s): Fang Wu   
Just Accepted Date: 14 July 2023   Online First Date: 11 September 2023    Issue Date: 12 October 2023
 Cite this article:   
Chaoyue Xiao,Wei Xiong,Yiting Xu, et al. Immunometabolism: a new dimension in immunotherapy resistance[J]. Front. Med., 2023, 17(4): 585-616.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1012-z
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I4/585
Fig.1  Overview of immune cell metabolism. Each type of immune cell and their resting or active state manifest completely divergent metabolic patterns. Abbreviation: Teff cell, effector T cell; Tm cell, memory T cell; Treg cell, regulatory T cell; NK cell, natural killer cell; DC, dendritic cell; TAM, tumor-associated macrophage; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway.
Immunocyte Glucose metabolism Lipid metabolism Amino acid metabolism
T cell
Teff cell Insufficient glycolysis downregulates tumoricidal effector molecule expression and triggers T cell anergy or even apoptosis [30,34] CD8+ T cells with incremental lipid ingestion overexpress PD-1 and enhance FAO, which impedes their effector functionality [41,42] There is too meagre Arg for T cells to mediate antineoplastic immunity, which promotes tumor growth and resistance to immunotherapy [46–49]
Tumor-derived lactate blunts anti-tumor immunity by varying pyruvate utilization and intercepting succinate signaling in CD8+ T cells [40] CD36 mediates FA ingestion by CD8+ TILs, which engages in lipid peroxidation and ferroptosis, culminating in adynamic tumoricidal capability [43,44] Trp deprivation represses T cell tumoricidal immunity, and Trp-associated metabolite accruement foments tumor evasion [50]
Underproductive PEP is inimical to T cell immunosurveillance [28] Cholesterol accumulation in the cytoplasm triggers the overexpression of inhibitory checkpoints and the functional exhaustion of CD8+ TILs [45] Due to the lack of Gln, Teff cells are irresponsive and Th1 and Th17 differentiation are repressed [29,51,52]. Dual lack of Asp and Gln spawns mass T cell death [53]
Met starvation embodies in meager Met and SAM, defective T cell function and survival [54,55]
Cys/Cys-Cys deprivation spawns T cell dysfunction and exhaustion by disrupting redox balance [56,57]
Treg cell Foxp3 lessens glycolysis in Treg cells, which allows them to be free from lactate limitation [58] Treg cells ingest exogenous FAs and elevate FAO to establish immunosuppression [42,60]
Treg cells exploit lactate within the TME to sustain immunosuppression [59] FAS mediated by FASN is conducive to the functional maturation of Treg cells [61]
SREBPs are overexpressed in Treg cells and participate in PD-1 overexpression [62]
Tm cell Tm cells depend upon intrinsic mobilization of FAs, utilize short- or medium-chain FAs, engage FAO to a greater extent [63–65]
NK cell Deprived amino acids repress mTOR signaling and glycolysis in NK cells, blunting their effector function [66] The intracellular lipid droplet accumulation profoundly inhibits NK cell cytotoxicity and metabolic bioactivity [70] The expression of ARG1 in the TME exhausts the Arg available for the antineoplastic response of NK cells [13]
Accrued SREBP inhibitors in the TME and overexpressed FBP1 in NK cell attenuate glycolysis and then NK cell cytotoxicity [67,68]
Extracellular accumulation of ADO inhibits OXPHOS and glycolysis of NK cells, which suppresses their cytotoxicity [69]
DC Impaired glycolysis in DCs inhibits their antigen presentation, cytokine generation, T cell stimulation [71] Lipid droplets accrue in DCs owing to either de novo FAS or intake from plasma, blunting antigen presentation [76,77] The entwined pathway between IDO1 and ARG1 in DCs leads DCs toward a more immunosuppressive state [84]
T cells activated by DCs compete for glucose, which represses glycolytic activity of DCs [72,73] The accrued ROS in DCs oxidizes lipids and blunts presentation capability and thus T cell priming [78,79]
The low pH of TME accentuates mitochondrial respiration while attenuating glycolysis in DCs [74,75] Lipid peroxidation elicits the UPR and ER stress responses, hindering effector molecule trafficking and T cell priming [80]
FAs accumulation intensifies FAO in DCs, leading tumor toward a more immunotolerant state [81]
PGE2 yielded by tumor cells and intratumoral DCs impedes DC antigen presentation [82,83]
Macrophage
M1-like TAM In the onset inflammatory phase of tumor initiation, TAMs manifest a more glycolytic characteristic that drives TAMs toward M1-like TAMs [85–87] FA intake and FAO are abated in M1-like TAMs, whereas FASN plays an indispensable role in the induction of M1-like TAMs [88,89]
M2-like TAM In the later phase of tumor progression, glucose depletion and lactate accruement skew the TAMs to underscore OXPHOS, boosting M2-like TAMs expansion [85–87] FAO and mitochondrial biogenesis in M2-like TAMs are reinforced to fuel incremental OXPHOS essential for M2-like TMAs activation [88–90] M2-like TAMs overexpress ARG1 that speedily catabolizes Arg and then stunts T cell activation, thereby contributing to immunosuppression [91]
The high expression and secretion of IDO in TAMs reinforce their M2-like polarization by yielding Kyn [92]
High levels of GLS are spotted in M2-like TAMs to maintain M2-like phenotype [93]
MDSC When MDSCs are confronted with tumor-derived factors, they upregulate glycolytic genes and ingest much glucose [94–96] Enhanced exogenous lipids ingestion and FAO enhance the immunosuppressive functions of MDSCs [98] Arg is deprived by MDSCs expressing ARG1, iNOS and CAT2, which leads T cells to fail to recognize antigens [101]
The high glycolysis of MDSCs produces CIMs and nucleotides to sustain immunosuppression [97] MDSCs with lipid overload have greater immunosuppressive effect on CD8+ T cells [99] The antineoplastic effects of T cells are significantly subdued by sequestering Cys by MDSCs [102]
The cholesterol profile of MDSCs is reshaped to reinforce their immunosuppression [100] MDSCs overexpress IDO under the induction of inflammatory cytokines [103]
The incremental Gln ingestion in MDSCs is chiefly utilized in glutaminolysis, thus promoting MDSC recruitment in the myeloid lineage around the TME [104]
Tab.1  Immunometabolism of tumor-infiltrating immunocytes
Fig.2  Resistant mechanism of immunotherapy: glucose metabolic reprogramming of immune cells within the TME. In the TME, tumor cells interfere with immune cell function by forcing immune cells to reprogram glucose metabolism. Specifically, metabolically highly active tumor cells deplete large amounts of nutrients (e.g., glucose and amino acids), which represses glycolysis of CD8+ T cells, NK cells, and TAMs by limiting the availability of glucose to CD8+ T cells and TAMs and amino acids to NK cells, and generate immunosuppressive metabolites (e.g., lactate, ADO), which attenuates glycolysis of DCs while accentuating mitochondrial respiration by acidifying the TME, sustains immunosuppressive identity of Treg cell by exploiting lactate by various metabolic enzymes, skews M1-like toward the polarization of M2-like TAMs by underscoring OXPHOS, and inhibits OXPHOS and glycolysis of NK cells by activating A2AR by ADO. When MDSCs are confronted with tumor-derived factors, they upregulate glycolytic genes and thereby ingest glucose as the greatest capability as possible. The glucose metabolic reprogramming ultimately emasculates the effector function of CD8+ T cells, DCs, NK cells, M1-TAMs, while invigorating the immunosuppressive function of Treg cells, M2-TAMs, and MDSCs, which contributes to immunotherapy resistance. Abbreviations: TME, tumor microenvironment; PD-1, programmed cell death-1; Gzms-B/C, granzymes B and C; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor β; GSK3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; PEP, phosphoenolpyruvate; MEs, metabolic enzymes; TCR, T cell receptor; TAM, tumor-associated macrophage; Treg cell, regulatory T cell; MDSC, myeloid-derived suppressor cell; DC, dendritic cell; NK cell, natural killer cell; ROS, reactive oxygen species; GLUT, glucose transporter; TIGIT, T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; SREBP, sterol regulatory element binding protein; ATP, adenosine triphosphate; AMP, adenosine 3′-monophosphate; ADO, adenosine; A2AR, A2A receptor; 25-HC, 25-hydroxycholesterol; 27-HC, 27-hydroxycholesterol; HIF-1α, hypoxia-inducible factor 1α.
Fig.3  Resistant mechanism of immunotherapy: lipid metabolic reprogramming of immune cells within the TME. In the TME, tumor cells interfere with immune cell function by forcing immune cells to reprogram lipid metabolism. Specifically, metabolically highly active tumor cells cause a typical metabolic alteration called lipid accumulation within the TME by augmenting FAS, which has varying effects on immune cells. In CD8+ T cells, the growing CD36 mediates the ingestion of FAs, which engage in lipid peroxidation and ferroptosis, and cholesterol, which triggers the overexpression of PD-1, TIM-3, and LAG-3 in an ER stress-XBP1-dependent manner. Treg cells ingest FAs to elevate FAO, and overexpress SREBPs to further overexpress PD-1. NK cells upregulate CD36 and Scarb1 to possess lipid accumulation. The accrued ROS in DCs oxidizes bountiful lipids that accrue owing to either incremental FAS or intake from plasma. FA intake and FAO that accelerates M1-like TAMs polarization via activating NLRP3 are abated in M1-like TAMs, whereas FAO and mitochondrial biogenesis in M2-like TAMs are synchronously reinforced to fuel incremental OXPHOS essential for activation of M2-like TMAs. MDSCs enhance lipids ingestion by elevated CD36, MSR1, FATP to enhance FAO, and upregulate the LOX-1 by ROS, inflammatory cytokines and ox-LDL to induce ER stress. The lipid metabolic reprogramming ultimately emasculates the effector function of CD8+ T cells, DCs, NK cells, M1-TAMs, while invigorating the immunosuppressive function of Treg cells, M2-TAMs, and MDSCs, which contributes to immunotherapy resistance. Abbreviations: PD-1, programmed cell death-1; TIM-3, T cell immunoglobulin mucin-3; LAG-3, lymphocyte activation gene 3; XBP1, X-box binding protein 1; ER stress, endoplasmic reticulumstress; SREBP, sterol regulatory element binding protein; FAO, fatty acid oxidation; CPT1A, carnitine palmitoyltransferase 1A; TAM, tumor-associated macrophage; Treg cell, regulatory T cell; MDSC, myeloid-derived suppressor cell; DC, dendritic cell; NK cell, natural killer cell; FAS, fatty acid synthesis; ROS, reactive oxygen species; TCR, T cell receptor; PGE2, prostaglandin E2; IL-10, interleukin-10; FAs, fatty acids; OXPHOS, oxidative phosphorylation; Scarb1, scavenger receptor class B member 1; FATP, fatty acid transport protein; MSR1, macrophage scavenger receptor 1; Ox-LDL, oxidized low-density lipoprotein; LOX-1, lectin-type oxidized LDL receptor-1; TAG, triacylglycerol; NLRP3, NOD-like receptor thermal protein domain associated protein 3.
Fig.4  Resistant mechanism of immunotherapy: amino acid metabolic reprogramming of immune cells within the TME. In the TME, tumor cells interfere with immune cell function by forcing immune cells to reprogram amino acid metabolism. Specifically, metabolically highly active tumor cells deplete large amounts of amino acids (e.g., Arg, Gln, Asp, Trp, Met, Cys), which limiting the availability of amino acid to CD8+ T cells, NK cells and DCs, and generate immunosuppressive metabolites (e.g., Kyn), which can be directly transferred into CD8+ T cells to overexpress PD-1 and directly activate AHR to boost Treg differentiation while blunting DC function and Teff cell proliferation. The expression of IDO and ARG1 is upregulated in DCs, leading DCs toward a more immunosuppressive state by an entwined pathway between IDO1 and ARG1. M2-like TAMs overexpress ARG1 that speedily catabolizes Arg, IDO and GLS that reinforce M2-like polarization. MDSCs overexpress ARG1, iNOS, CAT2 to deprive Arg, and IDO to deprive Trp, and system Xc– to deprive Cys/Cys-Cys. The incremental Gln ingestion in MDSCs is primarily utilized in glutaminolysis, thus promoting the recruitment of MDSCs. The amino acid metabolic reprogramming ultimately emasculates the effector function of CD8+ T cells, DCs, NK cells, M1-TAMs, while invigorating the immunosuppressive function of Treg cells, M2-TAMs, and MDSCs, which contributes to immunotherapy resistance. Abbreviation: PD-1, programmed cell death-1; IFN-γ, interferon-γ; TCR, T cell receptor; TAM, tumor-associated macrophage; Treg cell, regulatory T cell; MDSC, myeloid-derived suppressor cell; DC, dendritic cell; NK cell, natural killer cell; Arg, arginine; Kyn, kynurenine; Trp, tryptophan; Gln, glutamine; Asp, asparagine; Cys, cysteine; Cys-Cys, cystine; Met, methionine; ARG, arginase; IDO, indoleamine 2,3-dioxygenase; GLS, glutaminase; CAT2, cationic amino acid transporter 2; AHR, aryl hydrocarbon receptor; iNOS, inducible NO synthas.
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