Metabolism usually refers to a series of biochemical reactions, which is divided into two categories: catabolism and anabolism [1]. Different metabolic reactions coordinate with each other in vivo to jointly maintain the vital functions of the normal organism. Various substances produced can play a role in signal transductions and participate into various biological processes of the organism. For example, cAMP acts as an important second messenger [2, 3]. According to the differences in types of substrates generated or consumed, metabolism can be divided into carbohydrate metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism, etc. These different metabolic processes are not only involved in the maintenance of body homeostasis, but also associated with the development of diseases. For example, disorders of purine metabolism increase uric acid levels, and the resulted excess uric acidcauses inflammation and further leads to joint swelling [4, 5]. Overall, metabolicdisorders can induce many diseases such as diabetes, hyperlipoproteinemia, hypercalcemia, etc. The metabolism of cancer cells is different from that of normal cells [6]. For example, the Warburg effect is a metabolic process that exists in tumors. It is recognized as a way to gain energy through glycolysis even in the presence of abundant oxygen [7]. Metabolism dysregulation is one of the main hallmarks for the proliferation and invasion of tumors. In the absence of energy, cells may experience a series of function disordersthat even lead to cell death [8].

Cells have a life span and are subject to aging and death, and cell death is inevitable. Based on the different trigger mechanisms and processes, cell death can be divided into apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, cuproptosis, autophagy, etc. These forms of cell deaths affect the specifically relative cells on their physiological activities and survivals under many different mechanisms. For example, autophagy removes the damaged or senescent organelles by forming autophagosomes [9], while apoptosis is dependent on apoptosomes formation [10]. Cell death can also occur under some stress conditions that are not conducive to cell growth, such as hypoxia, lack of nutrients, or external stimuli. The survival of tumor cells can be affected by targeting cell death-related genes and can further be developed into a strategy for tumor therapy. For example, autophagy can be promoted by suppressing the autophagy-related mTOR pathway [11], thus supporting cancer cells growth. Autophagy not only supports tumor growth, but also can play the role as a tumor suppressor [12]. Under the suppression of MCOLN1/TRPML1, autophagy inhibits tumor metastasis through the TP53/p53 pathway [13]. Targeted cell death is currently used alone or in combination with other types of tumor therapies for cancer treatments [14, 15]. In recent years, as part of the cell death derives from metabolic stress and another part can be involved in metabolic regulation, the relationship between cell death and metabolism has received increasing attention in tumor development and treatment.

The tumor microenvironment is also essential for the development of tumors. The tumor microenvironment is crucial for tumor growth, so changes occurring in this microenvironment largely affects tumor cell survival and growth [16]. The microenvironment is rich and diverse and contains various tumor growth factors, extracellular matrices, and many other types of cells such as immune cells and fibroblasts [17]. These substances participate in tumor growth, development and immune processes [18]. Because of this, the tumor microenvironment has become one of the important targets for tumor therapy. Tumor immunotherapy is a very effective method that includes immune checkpoint therapy and CAR-T therapy, etc. Tumor cells can evade immunological cytotoxicity and immunological surveillance through immune checkpoints such as PD-1/PD-L1 or CTLA-4 [19,20,21]. For example, PD-1/PD-L1 receptor-ligand interactions are activated to suppress the immune function of T cells in tumors [22,23,24]. This process is called tumor immune escape [25, 26]. The tumor microenvironment, as the location where tumor cells exist, is involved in various tumor regulatory processes [27]. Immune checkpoint molecules and multiple immune cells, as well as other types of immune molecules present in the tumor microenvironment, make the tumor microenvironment important for immune checkpoint therapy or other immunotherapies [28, 29].

In this review, we will discuss how various metabolic pathways affect different cell death models, mainly focus on the impacts on tumor growths through some crosstalk, which will shed light on the possible connections between metabolic pathways and cell death models within tumor microenvironment. We also hope it will further provide some insights that may help readers investigate the relationships between metabolism and cell death in tumors.

Cell apoptosis affacted by metabolic activities and substrates during tumorigenesis

Apoptosis is one type of programmed cell death that is morphologically characterized by cell shrinkage, compact intracellular arrangement of organelles, nuclear division, and the appearance of apoptotic body in the cytoplasm [30]. Apoptosis is usually classified into two types: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway of apoptosis, also known as the mitochondrial apoptotic pathway, is caused by endogenous apoptotic signals such as endoplasmic reticulum stress, DNA damage, etc. In this pathway, modification of mitochondria structure and function causes apoptosis [30]. The extrinsic pathway of apoptosis is mediated by cell membrane death receptors and exogenous ligands [31]. Apoptosis requires the mediation of a series of key molecules, among which Bcl-2 family proteins and caspase family proteins, etc. play crucial roles. The Bcl-2 family members have different roles in apoptosis. Protein members such as BAX, and BAK have a pro-apoptotic effect, while BCL-2 and BCL-XL have an inhibitory effect [32]. Caspase proteins such as caspase-9 gain their activity through the cleavage of apoptosome, then involve into the hydrolysis of various intracellular proteins.

One of the most significant changes for tumor metabolism is aerobic glycolysis. Therefore, regulating the enzymes and proteins in glucose metabolism to change energy production rate can effectively modulate tumor growth. Regulation of the activity and function of glucose transporter (GLUT) proteins indeed influences apoptosis and further affects tumor growth [33]. GLUT1 regulates the PI3K/AKT signaling pathways to adjust tumor proliferation and apoptosis [34, 35]. AKT and p53 mutations exist in many different tumor types. Interactions between AKT and p53 in tumor cells affects apoptosis [36]. The p53-inducible gene TIGAR regulates the intracellular fructose diphosphate level. It also reduces the contents of reactive oxygen species to protect cells from ROS-related apoptosis [37]. In similar with the effects of deprivation and glucose metabolism blockage to cause insufficient energy production, abnormal activities of glucose metabolism-related enzymes can also cause this problem to reach to the same levels. For instance, pyruvate kinase, a key enzyme in glycolysis, inhibits apoptosis by supporting glycolysis. Besides repressing key enzymes during glycolysis, key enzymes in the citrate pyruvate cycle such as ATP citrate lyase (ACLY) also regulate apoptosis [38, 39]. In addition, ACLY can be deubiquitinated in the presence of USP30, which regulates the IKKβ-USP30-ACLY signaling axis and further effectively modulates lipid synthesis [40]. These studies show that correlations exist between multiple different metabolic processes and apoptosis. During the same time, many types of carbohydrate metabolism processes may get interactions through certain common enzymes or metabolites (Fig. 1) [41, 42]. Although it has not been fully proved that apoptosis can happen in all types of known carbohydrate metabolisms, it is still expected that the additional metabolic entry points for both regulating apoptosis in tumor cells and further influencing the ongoing tumorigenesis will be finally identified-after the specificities of interactions for different carbohydrate metabolism processes will be clarified.

Fig. 1

Metabolites, metabolic pathways and related metabolic genes that play the roles in apoptosis. Deficiencies of various substances involved in metabolism affect the relevant metabolic pathways and apoptosis. Glycolysis can be inhibited in the presence of Glut1 deficiency, which promotes the development of apoptosis. ACLY, a key enzyme involved in the conversion of citric acid to oxaloacetate and acetyl CoA, works with ACC1, an important enzyme in the process of acetyl-CoA production, to regulate the content of α-KG and promote ETV4, which in turn promotes apoptosis. ROS usually promotes apoptosis. When TIGAR inhibits the important oxidative ROS, apoptosis can be suppressed. Gln deletion synergizes with GLS1 to promote ROS-related apoptosis. Inhibition of NAMPT prevents the conversion of saturated fatty acids to monounsaturated fatty acids and promotes apoptosis. The red boxes represent negative regulators and the green boxes represent positive regulators

In addition to carbohydrates, amino acids are also important nutrients as well as important regulatory factors in the organism and tumor development. Similar to glucose, amino acid intakes can also influence apoptosis [43, 44]. Glutamine helps tumors to resist apoptosis, while its deficiency can induce apoptosis [45,46,47]. Glutamine deficiency and GLS filamentous polymers in cells together lead to asparagine deficiency and ROS-related apoptosis [47]. Other types of amino acids such as proline are also involved in the regulation of tumor cell apoptosis [48, 49]. Similar to glucose metabolism, amino acid transporters also adjust apoptosis in tumors, suggesting that uptake of energy or substances can effectively affect apoptosis. L-type amino acid transporter 1 (LAT1, SLC7A5) is upregulated in many tumors and inhibition of LAT1 function makes cancer cells more sensitive to apoptosis [50, 51]. Besides, some essential amino acids such as phenylalanine and methionine are involved in the regulation of apoptosis (Fig. 1) [52].

Palmitic acid is a highly abundant free fatty acid in the human body and is involved in the regulation of apoptosis [53, 54]. Lipids other than palmitic acid are also involved in the regulation of apoptosis. The oxidized low-density lipoprotein (OX-LDL) is closely related to endothelial cell damage and apoptosis [55, 56]. Besides apoptosis, lipids are also associated with tumorigenesis. ACAT1 acetylates GNAPT to regulate lipid metabolism and promotes hepatocarcinogenesis [57]. SREBP, a key factor in lipid synthesis, has been shown to be involved in apoptosis. SREBP and FASN targeting drugs can inhibit lipid synthesis to induce apoptosis in cancer cells [58]. The SREBP-regulated gene SCD is known to involve into apoptosis. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition can influence on the conversion from the saturated fatty acids to the monounsaturated fatty acids as well as on the expression of SCD, which further have an effect on apoptosis [59]. Other members of the lipid family and lipid metabolic processes have also been shown to be involved in the regulation of apoptosis in various contexts [60,61,62], demonstrating their indispensable role in regulating tumorigenesis.

Usually, apoptosis can be induced based on the relative mechanisms of either promoting or inhibiting the acquisition of energy. Mitochondria is a vital place for oxidative phosphorylation, which is required by both the aerobic oxidation of glucose and the β-oxidation of triglycerides [63]. Besides, mitochondria is also an important site for regulation of endogenous apoptotic pathway. Thus, modulation of structure and function of mitochondria of tumor cells can induce their apoptosis [64, 65]. Taken together, these studies suggest that it is feasible to influence tumor cell apoptosis through metabolism, either by directly reducing nutrient intake or affecting cellular nutrient utilization (Fig. 1). Tumor cell apoptosis regulated by metabolism does not just inhibit tumorigenesis, sometimes it appears to promote tumor growth. We may use this as a starting point to find more methods that can effectively inhibit tumorigenesis.

The crosstalk between metabolism and necrosis during tumorigenesis

Cell necrosis is defined as a pathological injury that is caused by factors such as physical damage, chemical stimulation or hypoxia. One of the most significant morphological features of necrosis is the rupture of cell membrane [66]. Due to the broken membrane, intracellular inflammatory substances are released into the surrounding environment and further induce an inflammatory response. Necrosis is a very common phenomenon in tumors [67]. Since the formation of blood vessels cannot keep up with a rapid expansion of the tumor tissue volume, a remarkable feature of solid tumors is that the internal tumor tissue is often devoid of oxygen and nutrients, thus making it more prone to necrosis.

Glucose metabolism is an important regulatory activity for tumors. It affects tumor growth by regulating apoptosis, autophagy, and other different kinds of cell deaths. Inhibition of glucose uptake is an important trigger for tumor necrosis, as cancer cells are more inclined to use glucose for glycolysis to gain energy [68]. During the process, the genes relative to energy metabolism is used as the inducing targets to regulate cell death. The transcription factor ATF4 also plays a role in necrosis that is regulated by glucose deprivation [69]. ATF4 is associated with p53 in different signaling pathways and influences the onset of other types of cell death in tumors [70, 71]. P53 also upregulates the expression of the lncRNA TRINGS in the context of glucose deficiency, allowing the increased TRINGS to bind STRAP for inhibiting STRAP mediated necrotic signaling [72]. Besides low glucose, high glucose levels can also regulate necrosis in many situations (Fig. 2) [73,74,75,76,77], demonstrating the broad role of glucose in regulating necrosis.

Fig. 2

Metabolites, metabolic pathways and related metabolic genes that take part in necrosis and necroptosis. Glucose starvation promotes necrosis through the transcription factor ATF4. In addition, it can act on p53, which regulates necroptosis by affecting the interaction between TRINGS and STRAP. Glucose deprivation also facilitates necroptosis by promoting the binding of mitochondrial DNA and ZBP1 to regulate MLKL, a key substance in the development of necroptosis. DHA supplementation with docetaxel (TXT) promotes necroptosis. As one of the key components of the necrosome that promotes the onset of necroptosis, MLKL function can be facilitated by GLTP. Very long chain saturated fatty acids participate in necroptosis by targeting MLKL. DMF promotes necroptosis by promoting the depletion of GSH, ROS generation and MAPK activation. The red boxes represent negative regulators and the green boxes represent positive regulators

Specific types of amino acids can promote tumor necrosis and achieve anti-tumor effects. Such amino acid induced necrosis occurs in prostate tumors [78]. Besides nutrients, other factors also regulate necrosis, such as hypoxia and reactive oxygen species [79, 80]. Hypoxia is an important necrosis inducing factor and converts the glucose deprivation-induced necrosis into AKT-dependent apoptosis [81]. As energy deficiency itself is one critical reason for tumor necrosis, we can curb the uptake and utilize of energy substances to induce necrosis [82, 83]. As a form of cell death that can be modulated by energy stress, it is feasible to influence necrosis in tumor cells through modulating energy-generating or depleting pathways.

The function of metabolism and necroptosis during tumorigenesis

Necrosis was once not considered to be regulated by genetics, but in subsequent studies, necrosis has been discovered as a gene-regulated cell death and designated necroptosis. Necroptosis is triggered by many protein kinases, including RIPK3, MLKL as well as other critical kinases [84]. Apoptosis-inducing receptors such as FAS, TNF receptor 1 (TNFR1), TNFR2, etc. also play a role in necroptosis. In addition, immune molecules associated with damage-associated molecular patterns (DAMP) stimulates the recognition receptors (PRRs) and leads to necroptosis [85]. Necroptosis as the regulated cell death mode is studied for its application in tumor therapy [15]. Necroptosis associated ZBP1 is regulated by the RNA editing enzyme ADAR1, thus affecting the actual efficacy of immune checkpoint blockade therapy [86]. During tumor prognosis, it has been shown that necroptosis promotes tumor repopulation after the treatment through RIP1/RIP3/MLKL/JNK/IL8 signaling pathway (Fig. 2) [87].

MLKL is one of the key regulators of necroptosis. Several studies have already uncovered the link between MLKL and energy stress, which provides good concept for the metabolic regulation of necroptosis. For example, overexpression of GLTP, a protein involved in the transport of sphingomyelin, induces phosphorylation of MLKL and leads to necroptosis [88]. Meanwhile, after glucose deprivation, ZBP1 is found to activate MLKL and promotes necroptosis in breast cancer cells [89]. Some substances, such as the members of the lipid family, can individually affect necroptosis. Docosahexaenoic acid (DHA), a member of the lipid family, is also related to necroptosis. DHA supplementation with docetaxel (TXT) promotes necroptosis in breast cancer cells [90]. Very long chain saturated fatty acids can also participate in the induction of necroptosis by regulating protein acylation [91]. In addition to the lipid, necroptosis with glutathione participation has also been reported. Dimethyl fumarate (DMF) can induce necroptosis by depleting GSH in colon cancer cells [92]. Moreover, AMPK of glucose dependent kinase regulates necroptosis and tumorigenesis through the activations of RIPK3 [93]. In addition, RIPK3 also links energy metabolism to necrosis and apoptosis [94], suggesting t