Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies

Abstract

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Keywords

CTLA-4 / PD-1 / PD-L1 / immune checkpoint blockade (ICB) / metabolic reprogramming / combined tumor therapeutic strategies

1 Introduction

Since the concept of immunotherapy first appeared in 1890, the development of cancer immunotherapy has slowly evolved. In 1984, a patient with metastatic melanoma received aggressive infusion of interleukin-2 (IL-2), which resulted in a marked decrease in visible tumor lesions [1]. This was the first case demonstrating that the growth of invasive cancers could be restrained by the stimulation of T lymphocytes, and this astonishing success sparked great interest in developing new strategies to reactivate quiescent T cells for cancer immunotherapy [2,3]. By the 1990s, the basic concept of cancer immunotherapy had been firmly established. It was known that neoantigens from cancer cells can be recognized by the immune system, but certain types of molecular interactions between tumor and immune cells often lead to immune attenuation; however, little was understood regarding the molecular mechanisms underlying these interactions and consequently, cancer immunotherapy has remained outside the mainstream of cancer treatment [4]. The situation has completely changed over the past decade: the discovery of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) as T cell immune checkpoint receptors has led to the concept of immune checkpoint blockade (ICB). The emergence of inhibitors that prevent CTLA-4 and PD-1 from recognizing their ligands, in order to reactivate suppressed T lymphocytes and enhance anti-tumor immunity, has had a broad impact on cancer patient survival. The first two PD-1-directed antibodies, nivolumab and pembrolizumab, were discovered in 2002 [5] and subsequently in 2011, ipilimumab, an antibody against CTLA-4, became the first approved ICB drug [6]. During the period from 2014 to 2017, inhibitors that block programmed cell death ligand-1 (PD-L1) emerged; and subsequently, ICB drugs targeting PD-1/PD-L1 rapidly prevailed as the first-line treatment for a wide variety of cancers [7], extensively transforming cancer therapeutic paradigms (surgery, chemoradiotherapy, and targeted therapy) and becoming the new pillar of cancer treatment.

The pivotal principle of ICB therapy is to block specific receptors or ligands that participate in the acquired peripheral immune tolerance process and to reactivate those attenuated immune cells to fight against cancer cells. Although ICB therapies have produced remarkably durable clinical responses in a wide variety of cancers, a large proportion of patients remain unresponsive to initial treatment or relapse after the initial response and subsequently develop acquired resistance [8]. Nowadays, owing to the growing number of studies regarding tumor immune evasion, we have a better understanding of the adaptive mechanisms used by tumor cells to overcome the harsh environment and resist ICB treatment. In fact, as a key feature of cancer metabolism, metabolic reprogramming in tumor cells changes many cellular processes to aid their adaptation to stressful conditions and to fuel growth and division. In 2011, reprogramming energy metabolism was listed as an emerging hallmark of cancer [9]. Otto Warburg first observed that, even in the presence of oxygen, cancer cells limit their energy metabolism largely to glycolysis, leading to a state that has been termed aerobic glycolysis [10].

Increased glycolysis produces a large number of metabolic intermediates and changes the metabolic profile of cancer cells, allowing the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids; and in turn, facilitates the biosynthesis of macromolecules and organelles required for the assembly of new cells [11]. For example, the glycolytic enzyme pyruvate kinase isoform M2 (PKM2) has been proposed to divert glycolytic intermediates toward the pentose phosphate pathway (PPP) and serine biosynthesis [12]. As an important source of nitrogen for amino acids and nucleotides, glutamine metabolism is upregulated by various oncogenic signaling pathways in cancer cells [13,14]. It is important to note that cancer cells proliferating in vitro consume glutamine far in excess of any other amino acid and are often dependent on extracellular glutamine for survival [15]. Cancer cells also show increased dependence on serine to support proliferation and survival [16,17]. Additionally, as a key component of the cell membrane, as well as an important signaling molecule and energy carrier, the metabolism of fatty acids (FAs) is crucial to cancer cells. It is known as a distinct metabolic “hallmark of the transformed phenotype,” and several lines of evidence suggest that targeting de novo FA synthesis may be an effective treatment for certain cancers [18]. Moreover, glycolytic intermediates can be secreted extracellularly in the form of signaling molecules or post-translationally modified proteins to modulate other cells present in the tumor microenvironment. Due to aerobic glycolysis, in which lactate dehydrogenase isoform A (LDHA) converts pyruvate to lactate, the lactate concentration in tumor tissue is 5–20 times higher than that in normal tissue (1.8–2.0 mmol/L) [19] and aids immune evasion of tumors via lactylation or as a signaling molecule [20]. Other metabolites such as acetyl-CoA can also influence tumor development through post-translational modifications.

Regulatory relationships between tumor metabolism and cancer immunity offer promising opportunities to enhance the efficacy of ICB therapy by targeting metabolic pathways and reshaping the tumor microenvironment (TME). In the present review, we discuss current data regarding certain pathways and metabolites related to cancer cell metabolic reprogramming that directly or indirectly interfere with immune checkpoints and the blockade efficiency of immune effector cells. We focus mainly on available studies and clinical trials to provide a comprehensive overview of the regulatory relationships between cancer cell metabolic reprogramming and three well-studied immune checkpoints—CTLA-4, PD-1, and PD-L1 (Fig.1).

2 Molecular and cellular functions of CTLA-4 and PD-1

The transmembrane protein CTLA-4 is characterized as an inhibitory receptor belonging to the well-studied CD28 immunoglobulin subfamily. It is also recognized as a key immune checkpoint and an important therapeutic target in several cancers. CTLA-4 is primarily expressed by T cells [21], but unlike CD28 that is constitutively expressed and presented at the membrane of naïve T cells, CTLA-4 is largely stored in intracellular vesicles and relocated to the cell membrane following T cell activation, after which it is rapidly internalized by endocytosis [22]. When presented at the cell membrane, both CD28 and CTLA-4 exist as homodimers and are capable of binding their ligands, CD80 and CD86 (also known as B7-1 and B7-2), respectively, via their extracellular MYPPPY motif [23]. CD80 and CD86 belong to the same family and are mainly found on the surface of specialized antigen-presenting cells (APCs). Activation of CD28 and CTLA-4 by CD80 or CD86 initiates a stimulatory or inhibitory signaling cascade in T cells, respectively. Intriguingly, CTLA-4 displays a higher affinity for CD80 and CD86 than does CD28 [24,25], thereby competing with CD28 to prevent downstream stimulatory signals. Moreover, CTLA-4 typically accumulates in the same region of the cell membrane as CD28, physically blocking its active site [26]. Owing to these functions, CTLA-4 is a crucial regulator of the immune system and plays a critical role in T cell homeostasis and self-tolerance. Research from the last decade has demonstrated that the expression, subcellular location, and stability of CTLA-4 in T cells are closely associated with tumor metabolism [27]; therefore, blockade of different pathways involved in cancer cell metabolic reprogramming will be instrumental in the advancement of ICB therapy.

Similarly, PD-1 is an important immunosuppressive molecule expressed mainly by immune cells including T cells, B cells, dendritic cells, natural killer (NK) cells, and tumor-infiltrating lymphocytes. However, unlike CTLA-4 that negatively regulates T cell activation during the initial phase of antigen presentation, PD-1 is constitutively expressed on T cells during long-term antigen exposure and regulates the effector phase of T cell responses. Therapies targeting PD-1 prevent immune evasion by activating T cells, in addition to blocking the binding of PD-1 ligands to PD-1 on the surface of tumor cells. Two ligands, PD-L1 (also known as CD274 or B7-H1) and PD-L2 (also known as CD273 or B7-DC) [28] have been reported to bind PD-1. PD-L1 is more widely expressed than PD-L2 in normal and tumor cells, and studies have shown that the association of PD-L1 on the surface of tumor cells with PD-1 on the surface of T cells leads to T cell dysfunction and exhaustion, which prevents cytotoxic T cells from effectively targeting tumor cells [28,29]. Therefore, a PD-1/PD-L1 blocking antibody that disrupts the PD-1/PD-L1 interaction can reactivate T cell function and clear cancer cells via the autoimmune system. Accordingly, many PD-1/PD-L1 antibodies have been developed for tumor immunotherapy; however, only a small fraction of cancer patients responds well to PD-1/PD-L1 blockade. It is necessary, therefore, to fully understand the upstream pathways that regulate the expression of PD-1 and PD-L1 to aid the design of novel strategies to enhance the clinical response rate and efficacy of immunotherapies [30].

3 Influence of cancer metabolic reprogramming on immune cell CTLA-4 and PD-1

As a hallmark of almost all cancers, the Warburg phenomenon is the classic tumor metabolic reprogramming process that shifts tumor metabolism from oxidative phosphorylation (OXPHOS) toward glycolysis [31]. Coincidentally, naïve T cells mainly rely on OXPHOS and fatty acid oxidation (FAO) to generate energy and support their needs. Following an antigen encounter, activated T cells switch to utilizing glycolytic metabolism to sustain effector functions [32]; and after antigen clearance, long-surviving memory T cells switch back to mitochondrial OXPHOS and FAO for energy generation [33]. Researchers have found that PD-1 blockade can promote glycolysis and decrease FAO in T cells [34], and may also reduce the number of functional effector T (T_eff) cells [35]. Moreover, coadministration of bezafibrate, a peroxisome proliferator-activated receptor γ (PPARγ) agonist used for hyperlipoproteinemia, has been found to improve the efficacy of PD-1 blockade treatment [36]. The metabolic competition in the TME that causes tumor metabolic reprogramming also profoundly affects the energy metabolism of neighboring immune cells. As a cellular energy receptor, AMP-activated protein kinase (AMPK) responds to low levels of ATP and maintains energy homeostasis in T cells. A recent study demonstrated that the molecular mechanism underlying the downregulation of PD-1 expression by AMPK in regulatory T (T_reg) cells involves the HMGCR/p38 signaling pathway to promote antitumor immunity [37]. Additionally, CTLA-4 has been proposed to be a metabolic biosensor for T cells to induce the downregulation of glycolysis [38], and CTLA-4 blockade promotes T_reg instability in low-glycolytic tumors [39].

Under hypoxia, a metabolic characteristic of the TME, at least two pathways control the expression levels of CTLA-4 and PD-1 in immune cells. The first pathway involves the upregulated transcription of hypoxia-inducible factor HIF-1α in T cells, which binds to the hypoxia response element and subsequently regulates the transcription of downstream CTLA-4 and PD-1 [40]. The second pathway is associated with augmented nucleotide metabolism through the generation of extracellular adenosine, which is mediated by the HIF-1α-CD39/CD73 axis in tumor cells [41]. Adenosine and ATP are normally present at very low levels in extracellular fluids [42]. Inflammation, ischemia, or cancer can cause the release of high levels of ATP, and extracellular ATP is then progressively dephosphorylated by ectonucleotidases such as CD39 and CD73, culminating in the formation of adenosine [43]. Extracellular adenosine triggers the accumulation of intracellular cAMP by binding to the G_s protein-coupled A_2A and A_2B adenosine receptors [44]. The adenosine-A_2AR pathway has evolved as a negative feed-back immunosuppressive mechanism [45]. Activation of A_2A adenosine receptor results in expansion of T_reg [46] and enhances PD-1 expression on both tumor-specific CD8⁺ T cells and T_reg cells [47]. Ciforadenant (CPI-444) is a potent and selective A_2AR antagonist, which induces antitumor response and augments efficacy of anti-PD-1/PD-L1 and anti-CTLA-4 treatment [48,49]. Blockade of CD73 significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and metastatic 4T1.2 breast cancer [47]. The binding of cAMP to cAMP-dependent protein kinase (PKA) initiates a cascade of phosphorylation events [50] that upregulates CTLA-4 and PD-1 expression in resting CD4⁺ and CD8⁺ T cells [51,52]. Moreover, under hypoxic conditions, cancer cells prefer to generate ATP through anaerobic glycolysis, and their high glucose demand is detrimental to the development and survival of neighboring immune cells [53]. The glucose deficiency in the TME caused by cancer cells forces CD4⁺ T cells to switch from aerobic to anaerobic glycolysis, which upregulates PD-1 expression and impairs IFN-γ production in CD4⁺ T cells [54]. Interestingly, a recent study showed that transient glucose restriction can increase carbon allocation to the PPP, thus enhancing the effector functions of CD8⁺ T cells and promoting tumor clearance in a murine model of lymphoma [55]. These data provide a fundamental basis for targeting the tumor Warburg effect to enhance the functions of effector T cells.

In addition to promoting the PPP, the increased glycolytic flux also increases the biosynthesis of amino acids, nucleotides, and FAs, producing a plethora of metabolites that influence nearby cells [56]. The Warburg effect in tumors also influences the glycolytic flux and results in the generation of immunosuppressive metabolites such as lactate, which can reduce tumor immune responses to ICB therapy. Previous studies have demonstrated that lactate exported from cancer cells can selectively target p38 and activate the JNK/c-Jun pathway in cytotoxic T cells [57], and the JNK/c-Jun pathway has been shown to upregulate PD-1 expression in CD4⁺ T cells [58]. Moreover, the accumulation of lactic acid not only stabilizes HIF-1α in immune cells [59] but also induces a pH decrease in the TME, which causes the upregulation of CTLA-4, IL-2, and IFN-γ expression and triggers immunosuppressive signaling pathways in T lymphocytes [60]. IL-2 and IFN-γ have also been reported to promote CTLA-4 expression [61]. Lactate is produced from pyruvate by the glycolytic enzyme LDH [62], and high LDH levels in tumors are associated with poor clinical outcomes [63]. LDHA-mediated aerobic glycolysis promotes IL-17a expression through enhanced H3K9 acetylation at the IL-17a gene locus [64], which subsequently increases the expression of PD-L1, CTLA-4, and indoleamine 2,3-dioxygenase-1 (IDO-1) [65].

As the building blocks for protein synthesis, amino acids are of equal importance to glucose for both tumor and immune cells, and a high availability of amino acids is essential for immune cell differentiation and tumor proliferation [66]. In tumor cells, tryptophan is the rarest amino acid but is vital for metabolic reprograming. The levels of tryptophan are precisely controlled in vivo, with the serotonin and kynurenine pathways mediating tryptophan catabolism via IDO-1 [67]. The T cell expression levels of inhibitory receptors and ligands, including CTLA-4 and PD-1 [68], are also upregulated by IDO-1. Interestingly, kynurenine, the main metabolite generated by tryptophan catabolism, can be secreted into the TME by cancer cells and activate the aryl hydrocarbon receptor (AhR) on T_reg cells [69], suppressing their function by promoting CTLA-4 expression [70]. This kynurenine-AhR pathway is also discovered between tumor-repopulating cells (TRCs) and CD8⁺ T cells. After activation, CD8⁺ T cells produce IFN-γ to stimulate the release of kynurenine from TRCs that have high IDO1 expression. Kynurenine is in turn absorbed by adjacent CD8⁺ T cells, leading to the induction and activation of AhR and subsequent upregulation of PD-1 expression [71]. Increased glutamine metabolism is another feature of tumor metabolic reprograming that maintains tumor proliferation and progression [72]. Intriguingly, the same metabolic pathway is also essential for T cell activation and proliferation [73]. In the TME, cancer cells typically compete with activated T cells to acquire glutamine, which has a negative impact on T cell antitumor immune responses; nevertheless, this provides the opportunity to improve ICB therapy by targeting glutamine metabolism in cancer cells. Previous reports have shown that glutamine deprivation impairs the function of CD8⁺ T cells by upregulating PD-1 expression [74], and the administration of glutamine can downregulate PD-1/PD-L1 expression in lymphocytes [75].

Fatty acid (FA) metabolism in cancer cells is critical for their proliferation, invasion, and metastasis [76], and also controls the expression levels of CTLA-4 and PD-1 in T cells. A low carbohydrate or ketogenic diet forces the body to retrieve energy from the catabolism of ketone bodies, which results in the restriction of tumor proliferation [77]. Analysis of data from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) revealed that glioma patients with a high expression of FA metabolism-dependent genes also have high expression levels of CTLA-4 and PD-1 and are sensitive to anti-CTLA-4 and anti-PD-1/PD-L1 immunotherapies [78]. Moreover, a standard ketogenic diet and supplementation with 3-hydroxybutyrate (3-HB), the principal ketone body, enhance the efficacy of CTLA-4 and PD-1 blockade [79]. Ketosis decreases the expression level of CTLA-4 on CD4⁺ T cells; and the expression levels of PD-1 and CTLA-4 are upregulated on CD8⁺ T cells, the expression of their ligands CD86 and PD-L1 is downregulated on APCs, which ultimately prolongs the systemic activation of effector T cells. In a murine model of melanoma, oral supplementation with 3-HB re-establishes the therapeutic response to anti-CTLA-4 treatment and significantly reduces tumor growth. Recent evidence demonstrated that FA and cholesterol metabolism in cancer cells influences the expression levels of several immune checkpoints in T and NK cells. Leptin has been reported to mediate triglyceride secretion and fat metabolism in adipocytes [80] and is usually expressed highly in obese individuals [81]. PD-1 expression was correlated with leptin levels in obese mice and was at least 2-fold higher in T cells from obese mice than that in T cells from normal mice. The high expression level of PD-1 diminished T cell proliferation and cytokine production and resulted in T cell exhaustion, which was partly driven by leptin signaling [82]. These findings advance our understanding of the roles of leptin mediated FA metabolism in cancer immunotherapies. Cholesterol is a vital component of cell membrane lipid rafts and is also required for T cell receptor clustering and the formation of immunological synapses (CTLA-4 and CD28 with CD80 or CD86) [83]. Although high expression levels of cholesterol in the TME induce PD-1 expression on CD8⁺ T cells, leading to T cell dysfunction [84], the reprogrammed cholesterol metabolism in malignant melanoma renders patients sensitive to anti-PD-1 therapy [85]. Cancer cells with reprogrammed FA metabolism also secrete proteins associated with lipid production and transportation into the TME via extracellular vesicles [86,87]. Studies have shown that the membrane localization and exocytosis of CTLA-4 in T cells requires the involvement of ADP ribosylation factor-1 (ARF-1), phospholipase D-1 (PLD-1), PLD-2, and activated guanosine triphosphatases (GTPases) [88].

In summary, tumor metabolic reprograming is generally beneficial to tumor progression and impairs the function of T cells by promoting CTLA-4 and PD-1 expression (Fig.2, Tab.1). On the other hand, high expression levels of CTLA-4 and PD-1 render patients more sensitive to ICB therapies. These works reveal the complexity of the crosstalk between tumor cell metabolism and T cell effector functions and highlight the importance of exploring new strategies co-targeting tumor metabolic reprograming and immune checkpoint inhibitors (ICIs).

4 Influence of cancer metabolic reprogramming on PD-L1

PD-L1 is an immune checkpoint molecule that regulates T cell proliferation and IL-10 secretion, and its expression was first discovered in the heart, placenta, lung, and skeletal muscle [89]. Subsequently, researchers found PD-L1 to be expressed on cancer cells and showed that its interaction with PD-1 on T cells led to the inhibition of T cell activation [90] and induction of T cell apoptosis [91], thereby inhibiting antitumor immunity. To date, several anti-PD-1/PD-L1 treatments have exhibited potent antitumor activities in various cancers [92]; however, a large proportion of cancer patients do not respond well to PD-1/PD-L1 blockade [93]. It is necessary, therefore, to elucidate new mechanisms that regulate PD-L1 with a view to developing potential combination therapies.

4.1 Glycometabolism

Tumor cells are characterized by high glucose uptake, increased glycolysis, high lactate production, and hypoxia, which generates a plethora of metabolic products that result in metabolic remodeling. Increasing evidence has revealed that cancer glycometabolism regulates PD-L1 at both the mRNA and protein levels (Fig.3).

Generally, rich nutrition is required for the rapid growth of cancer cells, among which glucose is the main source of energy. It has been shown that high glucose levels promote the dissociation of hexokinase (HK) 2 from mitochondria in human glioblastoma cells, which phosphorylates IκBα at T²⁹¹ and leads to μ-calpain-induced IκBα degradation and subsequent NF-κB-dependent upregulation of PD-L1. The combination of an HK inhibitor and an anti-PD-1 antibody significantly enhances the antitumor effect of immune checkpoint blockade [94]. Moreover, metformin, a widely used anti-diabetic drug, can activate AMPK, a serine/threonine kinase that functions to regulate energy homeostasis in tumor cells [95], to induce PD-L1 phosphorylation at S¹⁹⁵, leading to its abnormal glycosylation and degradation [96,97]. Further, p53 is activated in response to nutrient deficiency through the activation of AMPK and inhibition of AKT [98]. p53 can regulate PD-L1 by mediating the binding of miR-34 to its 3′ untranslated region in non-small cell lung cancer (NSCLC) [99]. In cancer cells, key enzymes involved in the citric acid cycle commonly harbor mutations and modulate the TME [100]. Succinate dehydrogenase assembly factor 5 can attenuate PD-L1 expression via the microRNA-200/ZEB1 pathway [101,102]. Moreover, the isocitrate dehydrogenase 1 mutant (IDH1-R132H; mIDH1) converts α-KG into 2-hydroxyglutarate (2HG). The accumulation of 2HG leads to DNA and histone H3 hypermethylation, resulting in an epigenetic reprogramming of the glioma cell transcriptome [103]. Inhibition of 2HG causes the upregulation of PD-L1 expression on mIDH1 glioma cells [104] and 2HG inhibition by mIDH1 inhibitor AGI-5198 combined with anti-PD-L1 immune checkpoint blockade leads to complete tumor regression in 60% of mIDH1 glioma-bearing mice [105].

The excessive proliferation of cancer cells results in a significant decrease in oxygen, generating hypoxic regions in the TME. Hypoxia confers plasticity and heterogeneity to tumors, leading to resistance to cancer therapies [106]; therefore, targeting hypoxia remains an attractive avenue for therapeutic intervention. PKM2 is responsible for converting phosphoenolpyruvic acid to pyruvate during glycolysis. In cancer cell nuclei, PKM2 regulates the expression of PD-L1 by binding to hypoxia-response elements in the PD-L1 promoter, thus creating an immunosuppressive TME [107,108]. HIF-1α is a key marker for hypoxia [109] that transcriptionally activates galectin-1, a β-galactose binding lectin [110], which together with carbonic anhydrase IX can be targeted to inhibit the progression of glioblastoma by reversing the Warburg effect [111]. Indeed, galectin-1 can reprogram the tumor endothelium to promote resistance of PD-L1 and galectin-9 to immunotherapy [112]. Furthermore, GB1107, a galectin-3 inhibitor, has been shown to augment the response to PD-L1 blockade [113].

Lactate is a rich oncometabolite secreted by tumors to asphyxiate surrounding immune cells and evade immune suppression [114]. Lactate can be sensed by its receptor GPR81, which leads to inhibition of the Hippo pathway kinase LATS and activation of the nuclear translocation of the YAP1/TAZ complex. Subsequently, TAZ binds to the transcription factor TEAD and induces PD-L1 transcription [115]. Moreover, lactate-induced activation of PD-L1 in tumor cells displays hallmarks of immune suppression, leading to reduced production of IFN-γ and the induction of apoptosis of cocultured T cells [115]. NAD⁺ is generated by increased LDHA expression [114], and NAD⁺ metabolism can regulate the expression of PD-L1. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD⁺ biogenesis, drives IFN-γ-induced PD-L1 expression in multiple types of tumors by activating Tet1. High NAMPT-expressing tumors are more sensitive to anti-PD-L1 treatment, and NAD⁺ replenishment enhances the efficacy of anti-PD-L1 antibodies in immunotherapy-resistant tumors; therefore, NAD⁺ replenishment combined with a PD-L1 antibody may be a promising therapeutic strategy for immunotherapy-resistant tumors [116].

4.2 Lipid metabolism

Aberrant lipid metabolism is prevalent in cancer metabolic alterations and strongly affects the expression and localization of PD-L1 (Fig.4). Dysregulation of lipid metabolism changes the oncogenic signaling pathways in cancer cells and impacts normal cell populations via the release of secretory components including lipids. Previous studies have demonstrated a strong correlation between lipid metabolism and PD-L1 levels in cancer cells [117–119].

Lipogenesis is highly activated in tumor cells to satisfy the needs of growth and proliferation. Acetyl-CoA is the main precursor for lipid synthesis, which is derived from citrate and acetate via ATP-citrate lyase (ACLY) and acetyl-CoA synthetase (ACSS), respectively [120,121]. Acetyl-CoA directly provides the acetyl group for the acetylation of PD-L1. The nuclear translocation of PD-L1 is inhibited by p300-mediated acetylation and promoted by HDAC2-dependent deacetylation [122]. ACLY is a pivotal enzyme bridging carbohydrate and lipid metabolism by producing acetyl-CoA from citrate for FA and cholesterol biosynthesis [123,124]. Encouragingly, the ACLY inhibitor, bempedoic acid, combined with anti-PD-L1 therapy has been shown to suppress tumorigenesis in a carcinogen-induced murine model of hepatocellular carcinoma [125]. Nevertheless, studies regarding the impact of ACSS-catalyzed acetate on PD-L1 are limited. Acetyl-CoA can be converted to FAs and cholesterol through a series of reactions. FAs are the substrates for PD-L1 palmitoylation, and targeting FA synthesis to limit PD-L1 palmitoylation offers a new auxiliary strategy for PD-L1 blockade. For example, pharmacological inhibition of fatty acid synthase (FASN) suppresses PD-L1 expression and palmitoylation, suggesting the potential use of FASN-PD-L1-targeted therapeutic strategies in bladder cancer [126]. Cholesterol originates from the condensation of two acetyl-CoA molecules by acyl coenzyme A-cholesterol acyltransferase (ACAT) [127]. The accumulation of cholesterol can activate c-Jun/AP-1 in response to p53 signaling [128]. AP-1 can bind to the PD-L1 enhancer and elevate PD-L1 promoter activity in Hodgkin’s lymphoma [129]. PD-L1 ubiquitination can be promoted by reducing cholesterol using the 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitor simvastatin or a cholesterol depletion reagent [130].

4.3 Amino acid metabolism

Amino acid metabolism is also elevated in cancer cells to satisfy proliferation and progression, which plays a crucial role in regulation of PD-L1 (Fig.5). Glutamine is second only to glucose in cancer metabolism and functions as a metabolite and regulator by donating its nitrogen and carbon atoms. During glutamine catabolism, glutamine is first converted to glutamate by glutaminase, and it has been demonstrated that glutaminase inhibitor 968 can increase the efficacy of PD-L1 blockade and boost the immune response in ovarian cancer [131]. Glutamine deprivation activates EGFR signaling via ERK1/2 and c-Jun, thus increasing PD-L1 levels in renal cancer [132]. Moreover, both EGFR and ERK1/2 inhibitors can reverse glucose deficiency-induced PD-L1 upregulation [133]. KRAS regulates glutamine metabolism by dampening the activity of glutamate dehydrogenase 1 (GLUD1), which is known to catalyze glutamate into α-ketoglutarate (α-KG) [134]. KRAS mutation also promotes PD-L1 recycling by enhancing the 5′ cap-dependent translation of ARF6 and AMAP1 mRNA in PDAC [135]. Cystine-glutamate exchange by the cystine/glutamate transporter (xCT) plays a vital role in orchestrating the balance of these amino acids in favor of tumor progression [136]. Sulfasalazine (SAS), an inhibitor of xCT, can activate PD-L1 and impair the efficacy of PD-1/PD-L1 blockade via the transcription factors IRF4/EGR1 [137]. Intriguingly, xCT is indispensable for antitumor immunity [138], indicating possible crosstalk between immunity and amino acid metabolism. Liver kinase B1 (LKB1) is a serine/threonine kinase that promotes glucose and glutamine uptake and utilization in an HIF-1α-dependent manner [139]. Suppression of LKB1 can enhance the transcriptional activity of PD-L1 in intrahepatic cholangiocarcinoma cells [140]. Moreover, MYC is a key factor in tumor metabolic reprograming [141], which also binds to the PD-L1 promoter and upregulates its expression [142].

Serine functions as an essential precursor for the synthesis of proteins, nucleic acids, and lipids to satisfy cancer proliferation. Transcription factor ATF3 can promote serine synthesis via the serine synthesis pathway (SSP) [143] and upregulates PD-L1 expression following deletion of the adenosine A1 receptor (ADOARA1) [144].

Arginine is a pivotal amino acid that participates in the urea cycle, in addition to the biosynthesis of nitric oxide, nucleotides, proline, and glutamate [145]. In TME, tumor cells compete with T cells for arginine. ADI-PEG20, a novel anticancer drug, is targeted toward arginosuccinate synthetase 1 (ASS1) to inhibit arginine synthesis in small cell lung cancer cells [146]. ADI-PEG20 increases the efficacy of PD-1/PD-L1 blockade by increasing PD-L1 expression and T cell infiltration as well as alleviating T_reg accumulation [146]. On the other hand, L-arginine supplementation [147] or arginase inhibition [148] can promote the function of immune cells and improve PD-1/PD-L1 blockade efficacy.

5-HTP (L-5-hydroxytryptophan), both a drug and a natural component of certain dietary supplements, is produced from tryptophan; and decarboxylation of 5-HTP yields serotonin, which is further converted to melatonin [149]. It has been reported that 5-HTP suppresses IFN-γ-induced PD-L1 expression in tumor cells by inhibiting the IFN-γ-induced expression of RTK ligands and the subsequent phosphorylation-mediated activation of RTK receptors and downstream MEK/ERK/c-Jun signaling, which leads to decreased PD-L1 induction [150].

5 Potential strategies for combined immunotherapy with metabolic intervention

There has been great progress in the use of a combination of molecules involved in cancer metabolism and immunotherapy, and it is intriguing whether cancer metabolism functions as a bridge between these molecules and immune checkpoints. Here, we summarized the efficacy of recent combined immunotherapy and metabolism-related molecules in both preclinical research and clinical trials (Tab.2 and Tab.3). Especially, the combination of A_2AR antagonist and anti-PD-L1 antibody increased recruitment of CD8⁺ T cells into the tumor and demonstrated antitumor activity in phase I clinical trial in a cohort of 68 patients with refractory renal cell carcinoma (RCC) [49]. Targeting key enzymes that participate in the modulation of cancer metabolism provides a novel strategy for increasing the efficacy of ICB. Blockade of LDHA improves the efficacy of anti-PD-1 therapy in murine melanoma [151]. Protein arginine methyltransferase 5 (PRMT5) is associated with oncogenesis through arginine-methylation-mediated control of gene expression, RNA splicing and DNA damage response. The combination of PRMT5 inhibition and ani-PD-L1 therapy increases the number of tumor-infiltrating T cells and enhances their function in lung cancer treatment [152]. The traditional Chinese medicine Saposhnikovia root extract, Prim-O-glucosylcimifugin, enhances the antitumor effect of PD-1 inhibitors by hindering arginine metabolism in B16-F10 and 4T1 murine tumor models and suppressing the citric acid cycle in myeloid-derived suppressor cells (MDSCs) [153]. Certain anticancer drugs have been successfully used in preclinical or clinical trials in combination with ICB; however, the specific correlation has not been elucidated. For example, in addition to regulating PD-L1 through post-translational modification [97] as mentioned above, metformin renders xenograft tumors responsive to ICB by reducing the hypoxic state [154]. Moreover, as a widespread hypoglycemic drug, metformin can relieve hyperglycemia by suppressing hepatic glucose production [155]; therefore, it will be interesting to elucidate the mechanism by which metformin regulates the effect of ICB by remodeling metabolism. Remarkably, Platycodin D, a natural product isolated from an edible and medicinal plant, reduces PD-L1 expression in lung cancer cells by triggering its extracellular release, which opens an exciting avenue for cancer immunotherapy [156]. Moreover, Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 [157].

Furthermore, identification of molecules that regulate both cancer metabolism and immune checkpoints may represent the “holy grail” of anticancer therapy. In p53-deficient MEF cells, NF-κB promotes glycolysis by upregulating SLC2A3 [158]. The combination of anti-NF-κB antibody and ICBs is efficient for advanced prostate cancer [159]. As a multifunctional cytokine, TNF-α regulates and interferes with energy metabolism, especially lipid homeostasis [160]. It has been reported that IL-4 and TNF-α treatment leads to a strong synergistic induction of PD-L1 in RCC cells [161]. Further, a selective reduction in the TNF cytotoxicity threshold increases the susceptibility of tumors to immunotherapy [162]. EGF is essential for cell growth and proliferation [163] and upregulates large-sized glucosomes in cancer cells, promoting glycolysis-derived serine biosynthesis [164]. Coincidentally, an unbiased screen conducted in 2017 demonstrated that EGF acts as an inducer of PD-L1 acetylation, phosphorylation, and ubiquitination [165].

Mutations in growth factor signaling cascades are commonly found in cancer cells, leading to dysregulation of nutrient metabolism. There exist three pathways downstream of EGFR: MAPK, PI3K/AKT/mTOR, and IL-6/JAK/STAT3 [166]. Abnormal activation of the PI3K/AKT/mTOR pathway can increase PD-L1 expression, with more detailed regulation at the post-transcriptional and translational levels relying on 4E-BP1, STAT3, NF-κB, c-MYC, and AMPK [167]. EGFR can also positively regulate IL-6/JAK/STAT3-dependent PD-L1 expression and cell proliferation in NSCLC [168]. STAT3, STAT5, and STAT6 expression is typically upregulated in cancer, and these proteins participate in the regulation of glucose transporters HK2, ENO1, PKM2, and LDHA, which are vital for glucose metabolism in cancer cells [169]. Additionally, there is crosstalk between the JAK2-STAT1 and PI3K-AKT pathways, and PI3K blockade can both downregulate PD-L1 and enhance the anti-proliferative effect of IFN-γ [170]. Moreover, deactivating the MAPK pathway with the EGFR inhibitors, cetuximab and erlotinib, or the MEK 1/2 inhibitor, selumetinib, prevents the EGF- and IFN-γ-induced upregulation of PD-L1 in NSCLC [171].

Further, specific molecular-targeted agents that have a differential effect on tumor versus T cells may represent a novel breakthrough in cancer treatment. Glutamine is essential for tumor growth, and the glutaminase inhibitor JHU083 has been demonstrated to simultaneously arrest glycolysis and oxidative phosphorylation in murine cancer cells while enhancing T cell oxidative phosphorylation. Increased efficacy was observed with the use of JHU083 in combination with PD-1 antibody therapy [172]. Due to hypoglycemia and hypoxia in the TME, CD8⁺ T cells enhance PPAR-α signaling and the catabolism of Fas, which is different from cancer cells. Researchers have found that the PPAR-α agonist fenofibrate enhances the therapeutic effect of PD-1 blockade in melanoma [173].

6 Perspective

Immunotherapy, especially checkpoint blockade targeting CTLA-4 and PD-1/PD-L1, has provided a promising opportunity for cancer treatment. Despite current ICB strategies achieving a long-term response in the treatment of several cancers, a significant proportion of patients do not benefit; therefore, it is imperative to explore new therapeutic strategies to further enhance the efficacy of immunotherapy. Most ICB therapies directly target immune effector cells rather than cancer cells, the latter of which have distinct metabolic signatures, including abnormally activated metabolic pathways and multiple metabolites, allowing their adaptation to the hostile TME and the mediation of nearby immune cells. Thus, metabolic interference between cancer cells and immune cell populations appears to be a determining factor in the efficacy of immunotherapy.

However, there remain several barriers in the combination strategy of metabolic interference and immunotherapy. The first key issue is that different types of tumors may benefit from distinct metabolic pathways; therefore, treatment strategies should be tailored to each cancer. Additionally, many of the metabolic pathways required by cancer cells are also indispensable for inflammation-related immune function, and metabolic interference can be counterproductive. Moreover, many metabolic pathways can have context-specific effects, with metabolic interference in different TMEs leading to different outcomes for both tumor and immune cells.

Recently, numerous studies have reported the use of cancer metabolic interference in conjunction with ICB therapies, which have shown encouraging outcomes for a wide range of cancers; however, the molecular mechanisms underlying the success of these strategies remain unclear. In the present review, we discussed several points: (1) the metabolic competition between tumor and immune cells in the TME; (2) the differences in metabolic reprogramming between these cells; (3) the different effects of metabolic processes on the expression levels of CTLA-4 and PD-1/PD-L1 in immune cells and tumor cells; and (4) T_eff and T_reg cells and the effect of targeting specific metabolic pathways and metabolites in the TME on the tumor immune response. We summarized the specific metabolic enzymes, pathways, and metabolites that function in both tumor metabolism and immunity, and further discussed that targeting these molecules can modulate both cancer and immune metabolism. Additionally, we outlined how specific metabolic enzymes, pathways, and metabolites regulate the expression and stability of CTLA-4 and PD-1/PD-L1 during tumor metabolic reprogramming, providing a reference for future studies devoted to exploring the molecular mechanisms underlying the combination of tumor metabolic interference and immunotherapy. However, a major impediment in immunotherapy is the discrepancies in cancer metabolism between mouse model and human. Thus it is difficult to recapitulate the efficient combined therapy from preclinical studies to clinical trials [174]. It is necessary to utilize different preclinical models such as syngeneic models, genetically engineered mouse models, and humanized PDX models to represent the human malignancy and assess responsiveness to immunotherapy.

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