In general, cancer cells exhibit altered metabolism, which is characterized by increased glucose uptake, a greater reliance on glycolysis, and changes in amino acid metabolism and the tricarboxylic acid (TCA) cycle (Fig. 1). Moreover, cancer cells often rely on the pentose phosphate pathway (PPP) to support nucleotide synthesis and antioxidant defense [21,22].

Glycolysis is a critical metabolic pathway that provides cancer cells with energy and building blocks for biosynthesis. Cancer cells upregulate glucose transporters (GLUTs) and glycolytic enzymes to increase glucose uptake and glycolytic flux. This phenomenon, known as the Warburg effect, is a hallmark of cancer metabolism [23]. The Warburg effect allows cancer cells to rapidly generate adenosine triphosphate (ATP) and produce intermediates for the biosynthesis of nucleotides, amino acids, and lipids. Moreover, the Warburg effect leads to the accumulation of metabolic intermediates that can promote cell growth and proliferation through various signaling pathways [23]. A hallmark of thyroid cancer metabolism is the upregulation of GLUTs, such as GLUT1 and GLUT3, which facilitate the uptake of glucose into cancer cells [24]. In addition, thyroid cancer cells exhibit increased expression of key glycolytic enzymes, including hexokinase 2 (HK2), phosphofructokinase (PFK), and lactate dehydrogenase (LDH), which contribute to a higher level of glycolytic flux [25]. Studies have shown that the activation of oncogenic signaling pathways, such as the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway and the MAPK pathway, can drive the upregulation of glycolytic enzymes in thyroid cancer cells [26]. Moreover, the hypoxic TME, which is a common feature of solid tumors, can also upregulate glycolysis in thyroid cancer cells by stabilizing hypoxia-inducible factor 1α (HIF-1α), a transcription factor that promotes the expression of glycolytic enzymes [27]. Refractory thyroid cancer refers to thyroid cancer that remains unresponsive or progresses despite RAI therapy, which is typically administered after initial surgical treatment [28]. Glycolysis has been implicated in the development of refractory thyroid cancer, as it plays a critical role in the metabolic adaptation of cancer cells to treatment-induced stress [29]. A study found that refractory thyroid cancer cells exhibited higher rates of glycolysis than sensitive cells, and that this metabolic adaptation was associated with increased HK2 and LDH expression [30]. In addition, the activation of the PI3K/AKT/mTOR pathway has been implicated in the development of resistance to RAI therapy in thyroid cancer, and this pathway is known to upregulate glycolytic enzymes [31].

Amino acid metabolism also plays an essential role in CCM. Cancer cells upregulate amino acid transporters and amino acid metabolic enzymes to support the increased demand for protein synthesis and other cellular processes. Moreover, amino acids can also act as signaling molecules and promote cancer cell survival and growth through various signaling pathways. For example, the amino acid glutamine is an important source of energy and carbon for cancer cells, and it also promotes the activation of the mTOR signaling pathway, which is critical for cancer cell proliferation [32]. In thyroid cancer, increased amino acid transport and metabolism have been shown to contribute to the growth and survival of cancer cells [33]. Specifically, increased expression of the amino acid transporter L-type amino acid transporter 1 (LAT1) has been observed in thyroid cancer, facilitating the uptake of essential amino acids, such as leucine, for use in protein synthesis and energy production [34]. The activation of the mTOR signaling pathway, which is commonly observed in thyroid cancer, promotes amino acid metabolism by upregulating amino acid transporters and amino acid metabolic enzymes [35]. ATC is an aggressive and highly lethal form of thyroid cancer that is associated with significant alterations in amino acid metabolism. A study found that ATC cells exhibited increased expression of several amino acid transporters, including LAT1, and increased rates of amino acid uptake and metabolism [36]. This increased amino acid metabolism was associated with the activation of the mTOR signaling pathway and the upregulation of amino acid metabolic enzymes, such as glutaminase (GLS) and alanine transaminase [37,38].

The TCA cycle is a central metabolic pathway that generates ATP and provides precursors for biosynthesis. In cancer cells, the TCA cycle is often dysregulated, with some intermediate metabolites diverted to support biosynthesis or other metabolic pathways [39]. For example, the intermediate citrate is exported from the mitochondria and used for fatty acid synthesis, which is critical for the formation of cellular membranes [40]. Studies have shown that the activation of oncogenic signaling pathways, such as the MAPK pathway, can drive the upregulation of enzymes involved in fatty acid synthesis in DTC cells [41]. Moreover, dysregulation of the TCA cycle has been shown to contribute to the development of resistance to targeted therapies, such as BRAF inhibitors [42]. ATC cells exhibit increased expression of several key enzymes in the TCA cycle, including pyruvate dehydrogenase and citrate synthase; this upregulation contributes to the increased production of ATP and nicotinamide adenine dinucleotide phosphate (NADPH), which supports cancer cell proliferation and survival [43].

Glutamine is a non-essential amino acid that plays a critical role in CCM. Glutamine is a major source of energy and carbon for cancer cells, and it is also involved in the synthesis of nucleotides, amino acids, and lipids. Glutaminolysis is the process by which glutamine is converted to α-ketoglutarate, which can enter the TCA cycle and contribute to energy production and biosynthesis. In DTC, glutamine metabolism and glutaminolysis have been shown to be dysregulated, with cancer cells exhibiting increased expression of glutamine transporters and enzymes involved in glutaminolysis, such as GLS [44,45]. Moreover, the activation of the mTOR signaling pathway, which is commonly observed in DTC, promotes glutamine metabolism by upregulating amino acid transporters and metabolic enzymes [46]. In ATC, glutamine metabolism and glutaminolysis are also dysregulated, with cancer cells exhibiting increased expression of glutamine transporters and enzymes involved in glutaminolysis [26]. A study found that ATC cells displayed increased expression of the glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) and the GLS isoform glutaminase C, contributing to the increased utilization of glutamine for energy production and biosynthesis [47]. Moreover, the upregulation of glutaminolysis has been implicated in the development of resistance to chemotherapy in ATC [48].

Finally, the PPP is a metabolic pathway that generates NADPH and ribose-5-phosphate for nucleotide synthesis and antioxidant defense. The PPP plays a critical role in CCM, and alterations in PPP activity have been observed in thyroid cancer, including DTC and ATC [26]. Upregulation of the PPP has been shown to contribute to cancer cell proliferation and survival in DTC. A study found that DTC cells exhibited increased expression of enzymes involved in the PPP, including glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, which contributed to the increased production of NADPH and ribose-5-phosphate [49]. Moreover, the upregulation of PPP activity has been shown to be associated with the activation of the PI3K/AKT/mTOR pathway, which is commonly observed in DTC. Alterations in PPP activity have also been observed, with cancer cells exhibiting increased expression of enzymes involved in the PPP in ATC. ATC cells displayed increased expression of glucose-6-phosphate dehydrogenase and transketolase, contributing to the increased production of NADPH and ribose-5-phosphate [26]. Moreover, the upregulation of PPP activity has been implicated in the development of therapeutic resistance in ATC, as PPP activity can provide cancer cells with antioxidant defense mechanisms to protect against chemotherapy-induced oxidative stress [49].

Tumors are highly heterogeneous, but metabolic reprogramming in cancer cells seems to involve a common set of pathways to support anabolism, catabolism, and redox homeostasis. The PI3K/Akt/mTOR pathway is the central regulator of cellular energetics and metabolism and is responsible for increasing glycolysis and fatty acid synthesis via HIF-1α and sterol regulatory element-binding protein (SREBP) activation, respectively [50,51]. Malignant tumors co-opt this network, with mutations in upstream receptor tyrosine kinases, the PI3K catalytic subunit, downstream Akt kinase, and negative regulator phosphatase and tensin homolog (PTEN) being frequently observed in cancer. Hypoxia is also a frequent feature of tumors, as rapid proliferation often exceeds angiogenesis. To adapt to hypoxia, tumors upregulate HIF-1α signaling, which is a downstream effector of the PI3K/Akt/mTOR pathway [52]. Activation of the HIF-1α pathway in cancer cells leads to increased glycolysis, which can deplete glucose levels and reduce energy stores, resulting in increased intracellular adenosine monophosphate (AMP)/ATP levels [43]. This, in turn, activates the AMP-activated protein kinase (AMPK)-liver kinase B1 (LKB1) pathway, which stimulates catabolic pathways that produce ATP, mainly through upregulating oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis [53]. AMPK also increases cellular levels of nicotinamide adenine dinucleotide (NAD+), which activates sirtuin 1 (SIRT1) and downstream targets such as peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and forkhead box O (FOXO) transcription factors, promoting mitochondrial biogenesis and activity [54]. These mechanisms maintain energy stores and promote efficient ATP production in cancer cells. Studies have shown that the BRAF^V600E mutation can activate the MAPK/extracellular signal-regulated kinase (ERK) pathway, which in turn upregulates genes involved in glycolysis and glutaminolysis, leading to an increase in glucose and glutamine uptake and utilization in PTC cells [44]. In addition, the BRAF^V600E mutation has been shown to promote the expression of HIF-1α, a transcription factor that regulates cellular responses to hypoxia. HIF-1α can activate genes involved in glycolysis, angiogenesis, and apoptosis, and has been implicated in the development and progression of several cancers, including thyroid cancer [55]. BRAF^V600E also promotes the expression of GLUT1, which increases glucose uptake in thyroid cancer cells. This increased glucose uptake and utilization support the high energy demands of rapidly proliferating cancer cells [56].

Studies have shown that RET/PTC-positive PTCs display alterations in metabolic pathways, including increased glucose uptake and glycolysis, as well as increased lipid synthesis and uptake. The TPC-1 (human papillary thyroid cancer) cell line, a PTC cell line driven by the RET/PTC1 rearrangement that expresses the coiled-coil domain containing 6/rearranged during transfection (CCDC6/RET) fusion protein, demonstrates elevated levels of HIF-1α and its downstream targets, promoting glycolysis [57]. Furthermore, RET/PTC1 and RET/PTC3 have been shown to increase the expression of phosphoinositide-dependent kinase 1 (PDK1), which inhibits the activity of pyruvate dehydrogenase, a key enzyme in mitochondrial metabolism. This results in a shift towards aerobic glycolysis, leading to increased lactate production and secretion, which can contribute to the acidification of the TME and promote tumor growth [58].

Driver oncogenes play a critical role in the metabolic reprogramming of thyroid cancer. The oncogenic activity of c-MYC, which is encoded by the MYC gene, has been reported to promote aerobic glycolysis by upregulating lactate dehydrogenase A, GLUT1, and glycolytic enzymes including PFK-1 and enolase [59]. c-MYC also facilitates the uptake and catabolism of glutamine, which is a significant source of energy for cancer cells. The expression of genes essential for glutamine metabolism, including GLS, glutamine synthetase (GLUL), and the glutamine cell-entry transporter ASCT2 (SLC1A5), is induced by c-MYC [60].

Mutations in RAS oncogenes have been reported in 12%–16% of PTCs, predominantly in follicular-variant PTCs, 25%–30% of FTCs, and 20%–40% of poorly differentiated thyroid cancers (PDTCs), ATCs, and even follicular adenoma [6,61]. Among the RAS oncogenes, NRAS is the most commonly mutated isoform, followed by HRAS and KRAS [62]. The activation of the RAS signaling pathway can lead to changes in metabolic reprogramming in cancer cells [63]. An integrative multi-omics analysis of PTC with the BRAF^V600E mutation, FTC with RAS mutation, and ATC found that one-carbon metabolism and pyrimidine metabolism were upregulated in both PTC and FTC, and to a greater extent in ATC. All subtypes of thyroid cancer exhibited increased expression of serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. In that study, compared to PTC, FTC showed enrichment in branchedchain amino acid degradation and the TCA cycle, exhibiting shared but distinct metabolic features [64].

Specifically, KRAS mutations have been shown to enhance glucose uptake and glycolysis in an FTC cell line, potentially promoting tumor growth and survival [65]. Additionally, KRAS activation has been linked to increased glutamine metabolism and the diversion of glucose-derived carbon to support nucleotide biosynthesis [66]. Overall, RAS activation in thyroid cancer may contribute to metabolic remodeling, which supports tumor growth and survival.

Despite the progress in cancer treatment and the availability of multimodal therapy for advanced thyroid cancer, the emergence of resistance remains a major obstacle contributing to treatment failure. This section delves into how metabolic reprogramming in cancer cells contributes to therapeutic resistance in refractory and undifferentiated thyroid cancer.

Solid tumors often have a hypoxic and hypoglycemic core due to rapid growth, resulting in a nutrient-poor environment that hinders tumor growth. Tumor cells overcome this limitation by reprogramming stromal cells in the TME. Cancer-associated fibroblasts (CAFs) are a key stromal component that provides metabolic support to tumor cells, thereby facilitating tumor initiation, growth, invasion, and dissemination. This is achieved through metabolic reprogramming of CAFs, which release energetic substrates into the TME, a phenomenon known as “tumor-feeding” [82]. Several modes of tumor-feeding have been proposed, including the “reverse Warburg effect.” In this mode, CAFs undergo metabolic reprogramming toward a glycolytic phenotype, while the associated cancer cells are reprogrammed toward OXPHOS [83]. CAFs produce lactate, which is exported via the monocarboxylate transporter-4 (MCT4) into the TME and taken up by tumor cells via the MCT1 transporter. In advanced PTC, MCT4 expression was found to be higher than in low-stage disease [84]. CAFs upregulate glycolysis-related enzymes, such as HK2 and 6-phosphofructokinase liver type (PFKL), which is thought to occur via signaling with plateletderived growth factor and transforming growth factor β (TGF-β) [83]. In addition to lactate, CAFs also supply tumors with glutamine. For example, CAFs in the ovarian tumor core undergo metabolic reprogramming, leading to the upregulation of glutamine anabolism to supply tumor cells in regions of glutamine scarcity. The glutamine released into the TME is subsequently taken up by cancer cells and converted to glutamate, which fuels the TCA cycle and supports energy production in cancer cells [85]. Apart from the direct release of metabolites into the TME, stromal cells have also been reported to fuel cancer metabolism by releasing metabolites carried in exosomes. These CAF-derived exosomes fuel cancer metabolism by supplying amino acids, lipids, and TCA cycle intermediates [86]. Similarly, in the context of thyroid cancer, CAFs release factors that activate the Src/Akt pathway in quiescent fibroblasts around ATC cells, enhancing CAF markers and GLUT1 expression. These factors also increase proliferation and invasiveness, and induce the epithelial-to-mesenchymal transition in FTC cells, thereby promoting tumorigenic alterations in thyroid cancer (Table 1) [87].

Metabolic remodeling in thyroid cancer can affect CAFs and the TME. The metabolic reprogramming of cancer cells can induce changes in the TME, leading to the activation of CAFs and promoting tumor growth and invasion. CAFs, in turn, can also reprogram their metabolism to support the energy needs of cancer cells, further contributing to the altered metabolism of the TME. This metabolic shift can also promote the secretion of cytokines and growth factors by CAFs, further modulating the TME and promoting tumor progression [85]. Therefore, targeting the metabolic crosstalk between cancer cells, CAFs, and the TME may offer a potential therapeutic strategy for thyroid cancer.

ECs play an important role in tumor angiogenesis by providing oxygen and nutrients to cancer cells. The metabolic signatures of ECs are altered in cancer, and the vascular EC function is modulated by metabolites [88]. Tumor paracrine signaling promotes a glycolytic phenotype in ECs by upregulating surface GLUT1 and PFKFB3, which activates PFK-1 to further increase glycolysis [89]. Lactate, which is enriched in the TME, triggers tube formation in ECs via HIF-1α-dependent nuclear factor κB (NF-κB) activation [90]. Amino acids also play a role in EC proliferation and migration. Glutamine is required for TCA cycle anaplerosis and non-essential amino acid synthesis, and depletion of glutamine or inhibition of GLS1 causes vessel sprouting defects due to impaired EC proliferation and migration [46]. Glycine and serine are also required for vascular endothelial growth factor (VEGF) signaling and mitochondrial function in ECs. Finally, fatty acids supply the carbon needed for deoxynucleotide triphosphate (dNTP) synthesis during EC sprouting, and altered CCM may affect fatty acid availability to support EC proliferation [91]. Overall, these changes in EC metabolism may contribute to the pathogenesis and progression of thyroid cancer.

The immune system plays a crucial role in tumor development and progression, with bidirectional crosstalk that can either inhibit or promote tumor growth (Fig. 2). An effective immune response depends on rapid adaptation to stimuli through metabolic reprogramming of immune cells [92,93]. During T cell activation, there is a metabolic shift from predominantly OXPHOS in resting T cells to increased glycolysis in activated T cells, facilitated by the upregulation of GLUTs and glycolytic enzymes [94]. This metabolic switch, known as the Warburg effect and similar to the reprogramming observed in cancer cells, enables rapid ATP production, supporting T cell proliferation, cytokine secretion, and effector functions. Additionally, activated T cells increase the uptake and utilization of amino acids and fatty acids for the biosynthesis of proteins, nucleotides, and lipids necessary for cell division and differentiation. However, in the TME, tumor cells can compete with T cells for essential nutrients, such as glucose and glutamine, which can impair T cell metabolism and function [95]. Additionally, the high production of metabolites by tumor cells, such as lactate and kynurenine, can create an immunosuppressive environment and induce the polarization of immunosuppressive T cell subsets, such as Tregs, exhausted T cells, and myeloid-derived suppressor cells (MDSCs) [86,96]. Overall, altered metabolic reprogramming in cancer can both deprive T cells of essential nutrients for anti-tumor activity and induce polarization of immunosuppressive T cell subsets, leading to T cell dysfunction and impaired anti-tumor immunity, and allowing the cancer to evade the immune system and proliferate.

Altered metabolic reprogramming in cancer can impair the function of natural killer (NK) cells and neutrophils, which are key components of the innate immune system, by inducing nutrient scarcity and producing cancer metabolites that impair anti-tumor immunity. The TME creates an immunosuppressive environment that inhibits the function of NK cells and neutrophils mediated by TGF-β, interleukin 10 (IL-10), and prostaglandin E2 (PGE2) released from tumor cells and other cells within the TME [97]. Furthermore, recent studies have shown that NK cells and neutrophils can also undergo metabolic reprogramming in response to the TME. For example, in the TME, NK cells can shift their metabolism towards glycolysis, which impairs their cytotoxic function [98]. Kynurenine secreted by thyroid cancer cells enters NK cells via aryl hydrocarbon receptor (AhR) and activates the STAT1 and STAT3 pathways, reducing the expression of activating receptors, natural killer group 2, member D (NKG2D) and natural killer cell p46-related protein (NKp46) [99]. Concurrently, PGE2, also secreted by thyroid cancer cells, binds to prostaglandin E2 receptor subtypes 2 and 4 (EP2 and EP4) and inhibits the MAPK/ERK and NF-κB pathways, leading to decreased cytotoxicity and interferon-γ (IFN-γ) production (Table 1) [100]. Similarly, neutrophils in the TME also undergo metabolic reprogramming toward an immunosuppressive phenotype that supports tumor growth and progression [101].

The relationship between tumor-associated macrophages (TAMs) and cancer cells is complex, with both influencing each other’s behavior. TAMs can either potentially eliminate tumor cells or promote their survival, proliferation, metastasis, angiogenesis, and immune suppression. The specific impact of TAMs on tumor progression depends on their reprogramming within the TME, influenced by factors including hypoxia, local mediators (such as cytokines and growth factors), and metabolic products from cancer or other immune and stromal cells. One key factor driving this reprogramming is lactate, which activates the G-protein-coupled receptor 81 (GPR81) receptor on TAMs, initiating a series of events that activate the AKT1/mTOR pathway, leading to increased aerobic glycolysis (Table 1) [102]. Another study has reported that TAMs in thyroid cancer undergo a distinct metabolic shift, involving increased fatty acid synthesis, elevated glycolysis, and the release of cytokines, including both pro-inflammatory (tumor necrosis factor-α and IL-6) and immunosuppressive (IL-10) types [103,104]. These findings highlight the profound impact of metabolic reprogramming on TAMs, emphasizing their significant role in the TME.

The immune checkpoints programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) negatively regulate T cell function, limiting T cell activation to prevent excess inflammation and tissue damage [105]. In cancer, programmed death-ligand 1 (PD-L1) and PD-L2 ligands are upregulated on cancer cells to dampen anti-tumor immunity. Engagement of PD-1 by its ligands results in the recruitment of protein tyrosine phosphatases such as Src homology region 2 domain-containing phosphatase-2 (SHP2), which antagonizes downstream pathways required for metabolic reprogramming of activated T cells, including PI3K/Akt, Ras, ERK, Vav, and phospholipase C gamma (PLCγ) [106]. PD-1/PD-L1 signaling is known to suppress glycolysis and promote lipolysis and fatty acid oxidation, and anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have shown to upregulate glycolysis and promote IFN-γ production [107,108]. Based on this understanding, the combination of PD-1 blockade therapies with interventions targeting cellular metabolism has the potential to enhance the effectiveness of anti-tumor immune responses. Overall, the function of PD-1 and CTLA-4 in antagonizing key metabolic pathways in T cells provides a mechanism by which tumors limit anti-tumor immunity and highlights the potential for metabolic invigoration of T cells by immune checkpoint blockade.

PD-L1 expression has been found to be higher in ATC than in other subtypes, and the tumor mutational burden is generally higher in ATC [109,110]. Different subtypes of thyroid cancer also have different immune infiltrates in the TME, with DTC having a lower immune infiltration dominated by regulatory T cells (Tregs) and fewer cytotoxic T cells, whereas ATC and MTC show robust immune infiltrates, including Tregs, MDSCs, and TAMs [111,112]. However, clinical trials with immunotherapy have shown limited efficacy, and there is a need for further investigation into new strategies, validation of predictive biomarkers, and better population selection for clinical trials in thyroid neoplasm [113].

Immunotherapy, while successful in treating several types of cancers, has shown comparatively limited efficacy in thyroid cancer [112]. This reduced effectiveness of immunotherapy in thyroid cancer is due to multiple contributing factors that lead to immune evasion and immunosuppression. One key aspect is poor tumor immunogenicity, a consequence of tumor editing, where tumors evolve to escape immune detection. Another contributing factor is the upregulation of immune checkpoint ligands, often exacerbated by the dysregulated expression of key metabolic enzymes such as pyruvate kinase M2 (PKM2) [114]. Additionally, the effectiveness of immunotherapy is compromised by the lack of tumor-infiltrating T cells due to the release of immunosuppressive cytokines and upregulation of immune checkpoint ligands induced by CAFs [115]. Moreover, CAFs are glycolytically active and release metabolic fuels into the TME, thereby feeding adjacent cancer cells and reprogramming cellular metabolism toward OXPHOS [82]. Finally, metabolic reprogramming of cancer cells not only affects the tumor’s mutation rate and antigenicity, but also contributes to an immunosuppressive tumor environment through nutrient competition with immune cells and production of cancer metabolites. These metabolic changes significantly impact both the behavior of the tumor cells and the effectiveness of immunotherapy in thyroid cancer.

Some studies have shown that thyroid cancer cells exhibit higher levels of glucose metabolism and glycolytic enzymes than normal thyroid cells, suggesting that targeting glycolysis may be a viable therapeutic strategy [26]. Additionally, some research indicates that inhibiting glycolysis can sensitize thyroid cancer cells to radiation therapy, a common treatment for thyroid cancer [75]. However, limited experimental evidence supports the use of glycolysis inhibitors for thyroid cancer, specifically ATC.

In a broader context, inhibitors of glycolysis present a promising strategy for cancer treatment. HK2, because of its role in maintaining high glycolytic rates, has emerged as a potential target. Known HK2 inhibitors such as 2-DG, 3-bromopyruvate, and lonidamine have been identified. Notably, 2-DG has shown promising outcomes as a single-agent therapy in phase I/II clinical trials [141,142]. PFKFB3, a significant regulator of glycolysis that is often upregulated in cancers, has inhibitors (e.g., PFK15 and PFK158) that have displayed anti-neoplastic properties in preclinical studies [143]. Moreover, small molecular inhibitors of GLUT proteins, including phloretin, STF-31, WZB117, and ritonavir, are under evaluation for their effectiveness against various cancers [144]. Interestingly, inhibiting GLUT selectively targets cancer cells that express high levels of the cystine-glutamate antiporter (xCT), revealing a metabolic vulnerability [145]. Despite these promising results, more research is needed to confirm the safety and efficacy of these inhibitors for clinical use.

Inhibiting OXPHOS can be beneficial for cancer treatment, particularly in combination with other therapies.