Breaking the vicious cycle: Multifunctional nanomaterials targeting Tumor metabolic reprogramming to overcome T cell exhaustion and bone repair failure in bone tumors

Abstract

Bone tumors establish a self-perpetuating vicious cycle wherein metabolic reprogramming (e.g., aerobic glycolysis, glutamine addiction) drives both T cell exhaustion and osteolytic damage. Tumor-derived lactate and nutrient depletion suppress T cell function while promoting osteoclast activation and inhibiting osteoblast differentiation. Reciprocally, bone damage releases immunosuppressive factors (e.g., TGF-β, and calcium) that further exacerbate T cell exhaustion, creating a pathological feedback loop. This review proposes the "Metabolic-Immune-Bone Network" (MIBN) as a framework for understanding this interplay. Crucially, multifunctional nanomaterials offer a promising strategy to disrupt this cycle. By precisely targeting metabolic pathways, they simultaneously suppress tumor growth and alleviate microenvironmental immunosuppression/acidosis. Their multifunctional design enables co-delivery of metabolic inhibitors, immune modulators, and osteogenic agents, thereby restoring T cell cytotoxicity and promoting bone regeneration. This dual “anti-tumor and osseous-preserving” functionality addresses the limitations of conventional therapies, shifting the paradigm from lesion-focused treatment toward holistic rehabilitation. This aligns with the “3R” strategy—Remodel, Repair, and Remove—highlighting microenvironment modulation, bone regeneration, and immune-mediated tumor clearance. Future advances in stimulus-responsive and metabolically targeted nanomaterials hold significant potential for breaking the MIBN-driven vicious cycle in bone oncology.

Graphical abstract

Metabolism-immune-bone network. This figure illustrates the central role of tumor metabolic reprogramming in the bone tumor microenvironment. It demonstrates how altered metabolism (e.g., lactate accumulation, glutamine depletion) drives T cell exhaustion (reduced proliferation/function) and bone destruction (osteoclast activation; osteoblast suppression), highlighting the dual impact on immunity and bone homeostasis as a basis for bone tumor targeted therapies. Created in BioRender. Guo, S. (2025) https://BioRender.com/ei185eq.

1. Introduction

Malignant bone tumors are serious diseases that affect human health. Bone tumors can be divided into two categories, primary and secondary, with osteosarcoma being the most common primary bone tumor, accounting for approximately 70 % of all primary bone tumors [[1], [2], [3]]. Metastatic bone tumors are more common in the clinic, especially in patients with advanced prostate, breast, or lung cancer [4]. Patients with bone metastasis are often accompanied by skeletal related events (SREs), including pathological fractures, spinal cord compression and intractable bone pain. In this regard, the current clinical treatment mainly adopts the therapeutic strategy of inhibiting osteoclast activity, such as bisphosphonate drugs and nuclear factor κB receptor activator ligand (RANKL) inhibitors. The auxiliary methods used include palliative radiotherapy and orthopedic stabilization surgery. However, although existing therapies can alleviate skeletal complications, they have limited effects on tumor regulation. Moreover, with the continuous improvement in the survival rate of patients with bone tumors after surgery, SREs have also received increasing attention. Therefore, the development of new therapeutic strategies with both anti-tumor activity and bone protection is highly important for improving the prognosis of patients (see Fig. 1).

Fig. 1.

Metabolism-immune-bone network. This figure illustrates the central role of tumor metabolic reprogramming in the bone tumor microenvironment. It demonstrates how altered metabolism (e.g., lactate accumulation, glutamine depletion) drives T cell exhaustion (reduced proliferation/function) and bone destruction (osteoclast activation; osteoblast suppression), highlighting the dual impact on immunity and bone homeostasis as a basis for bone tumor targeted therapies.Created in BioRender. Guo, S. (2025) https://BioRender.com/ei185eq.

Multifunctional nanomaterials are engineered platforms designed to simultaneously regulate distinct pathological processes—such as tumor metabolism, immune dysfunction, and skeletal degradation—within the bone tumor microenvironment. These materials integrate multiple functional modules, including metabolic inhibitors, immunomodulators, and osteogenic cues. Their design allows for targeted, combinatorial, and spatiotemporally controlled delivery of therapeutic agents, enabling synergistic anti-tumor activity and bone repair. This multifunctionality makes them ideal candidates for advancing from lesion-oriented treatment to holistic rehabilitation [5,6].

On the one hand, nanomaterials can precisely target tumor cells and related metabolic pathways, exerting highly efficient anti-cancer effects. For example, through surface modification and other technologies, nanomaterials can specifically recognize and bind to tumor cell surface markers to achieve precise targeting of tumor cells while reducing damage to normal tissues [7]. Considering that many drugs targeting the metabolism of tumor cells have indiscriminate toxicity, nanomaterials can complement their advantages [8,9]. In addition, some nanomaterials can interfere with the metabolic processes of tumor cells, such as inhibiting the utilization of glucose or glutamine by tumor cells, thereby cutting off the energy supply and material synthesis pathways of tumor cells and producing toxic substances, and restraining tumor growth from metabolic pathways [[10], [11], [12]]. On the other hand, in the aspect of bone preservation, many existing nanomaterials have the ability to promote bone tissue regeneration and repair. Some nanomaterials can simulate the microstructure and composition of natural bone tissue, providing a good scaffold for the adhesion, proliferation and differentiation of osteoblasts and inducing bone tissue regeneration [13]. It has also been found that specific nanomaterials can stimulate the differentiation of bone marrow mesenchymal stem cells into osteogenic cells by regulating the local microenvironment, increasing bone mass and repairing bone destruction [14]。More importantly, nanomaterials have great potential to integrate the above two functions to achieve the synergistic effect of anti-cancer and bone preservation. Therefore, the application of nanomaterials in bone tumors is expected to improve the prognosis and quality of life of patients with bone tumors through the "metabolic-immune-bone" regulatory network.

T cell exhaustion, as a key immunosuppressive mechanism in the progression of chronic diseases, stems from continuous antigenic stimulation and fundamentally weakens the host's defense ability. T cell exhaustion is driven by multiple factors, such as chronic TCR stimulation, cytokines present in the microenvironment (IL-10, IL-35, IL-6, and IL-27), and microenvironmental changes such as reduced nutrient supply and hypoxia [15]. At the molecular level, exhausted T cells exhibit a unique immunophenotype: reduced proliferative potential, epigenetic reprogramming, and metabolic dysregulation, accompanied by high expression of inhibitory receptors such as PD-1 and CTLA-4, and decreased effector function [16]. This multidimensional biological alteration results in significant impairment of effector functions such as cytokine secretion and cytotoxic activity. Notably, in the tumor microenvironment, such functional defects promote cancer immune escape by disrupting immune surveillance mechanisms, thereby accelerating primary tumor growth and metastatic spread.

Recent research has shown that targeting the regulatory network of T cell exhaustion has become a frontier in the field of tumor immunotherapy [17,18]. In some primary malignancies, such as osteosarcoma, the number of tumor-infiltrating lymphocytes (TILs) is known to be much greater than that in other sarcomas [19]. Therefore, in the context of these specific malignant tumors, treatment regimens targeting T cell exhaustion have even broader application prospects compared to other tumors.

The phenomenon of metabolic reprogramming in tumor cells shows multi-dimensional and complex regulatory characteristics. The essence of metabolic reprogramming is that malignant tumors achieve dynamic balance of energy supply and biosynthesis by remodeling metabolic network. This is what we call the remarkable metabolic reprogramming characteristic of malignant tumor cells [20]. Aerobic glycolysis (the Warburg effect) revealed by classical studies is only one part of this complex regulatory system. It is worth noting that tumor cells can exert metabolic pressure on non-tumor cell populations through competitive uptake of essential nutrients and regulation of tumor microenvironment components, and this metabolic interaction has been proved to be closely related to tumor malignant progression [21,22]. Therefore, this review systematically analyzes the two core metabolic pathways of aerobic glycolysis and glutaminolysis with a focus on: the accumulation of metabolites of the Warburg effect, and glutamine depletion in the microenvironment caused by tumors. We noted that alterations of these two metabolic pathways in tumor cells adversely affected both T cells and bone.

Based on these findings, we propose the hypothesis that there seems to be a close interaction network among tumor cell metabolic reprogramming, T cell exhaustion and bone tumor osteolytic destruction, with metabolic reprogramming at the center of this network. The breakthroughs in these research directions will provide theoretical basis for the development of new anti-bone tumor strategies targeting the metabolic-immune axis, as well as the research of bone regeneration based on metabolic regulation. This strategy reflects the “3R” concept: remodeling the microenvironment, promoting bone repair, and enabling tumor removal.

Collectively, this review elucidates the dual effects of tumor metabolic reprogramming in driving T cell exhaustion and bone repair impairment within the bone tumor microenvironment. We systematically dissect the underlying mechanisms through which dysregulated aerobic glycolysis and glutamine metabolism exacerbate immunosuppression and osteolysis. Crucially, we identify a pathological interplay wherein T cell dysfunction and bone damage mutually reinforce each other, establishing a self-perpetuating vicious cycle. To conceptualize this triad, we propose the Metabolic-Immune-Bone Network (MIBN) as a unifying framework, positioning tumor metabolism as its central regulator. Building upon this paradigm, we further highlight the potential of multifunctional nanomaterials to disrupt the MIBN cycle. By precisely targeting metabolic pathways, these advanced materials can simultaneously suppress tumor growth, reverse T cell exhaustion, and restore bone homeostasis—thereby enabling integrated anti-cancer and osteogenic functionality. This approach addresses critical limitations of conventional metabolic inhibitors and aligns with the evolving therapeutic shift from mere “lesion clearance” toward comprehensive “holistic rehabilitation” in bone oncology.

2. The dual effects of metabolic reprogramming of tumor cells

2.1. The dual effects of aerobic glycolysis

2.1.1. Mechanisms of the inhibitory action of aerobic glycolysis on T cells

Tumors with high glycolytic activity are able to suppress T cell immune function and lead to T cell exhaustion through a dual metabolic mechanism: one is microenvironmental glucose deprivation through accelerated glucose metabolism [23],and the resultant increased levels of lactate could cause metabolic toxicity [24,25]. The second is that lactic acid leads to the proliferation of regulatory T cells (Treg), which further leads to T cell exhaustion (Fig. 2).

Fig. 2.

Dual effects of aerobic glycolysis. Aerobic glycolysis has dual effects in the microenvironment of bone tumors. Tumor cells consume a large amount of glucose through enhanced glycolytic pathways, resulting in a reduction of glucose in the microenvironment. This state of glucose deficiency inhibits the glycolytic metabolism of T cells, thereby limiting their proliferation and effector functions. Meanwhile, a large amount of lactic acid produced during the glycolysis process of tumor cells enters T cells, resulting in the accumulation of lactic acid and protons within T cells and disrupting their metabolic balance. Treg has unique metabolic adaptability in a low-glucose environment and can utilize lactic acid as an energy source, thereby maintaining its high inhibitory function in the tumor microenvironment. These factors eventually lead to T cell dysfunction and exhaustion. On the other hand, lactic acid can directly dissolve hydroxyapatite in bone tissue and release calcium ions at the same time, promoting the differentiation of osteoclasts. Lactic acid and tissue acidification can also synergistically promote osteoclasts, further intensifying osteolysis.

By Figdraw.

The metabolic program of T cells is matched with functional requirements and is strictly regulated. Resting T cells efficiently produce ATP to meet the energy requirements of immune surveillance mainly through oxidative phosphorylation. However, when they are stimulated by antigens, costimulatory ligands or inflammatory cytokines, their metabolic pathways will be reprogrammed after entering the rapid proliferation phase. Upon activation, glycolysis and glutamine metabolism of T cells increase to produce biosynthetic precursors required for rapid cell growth and proliferation. These metabolic transitions are highly similar to metabolic reprogramming of tumor cells [26]. Thus, glycolysis within tumor cells results in the consumption of extracellular glucose, which limits the glucose supply to T cells. Reduced glucose availability leads to inhibition of glycolytic metabolism in T cells, leading to reduced effector function [27].

In addition to inhibiting T cells through metabolic competition, metabolic products such as lactic acid produced by tumor cells also have inhibitory effects. Activated T cells rely on glycolysis to generate energy to maintain effector function. This process requires the continuous excretion of lactic acid and protons to maintain intracellular pH homeostasis. However, excess lactate produced by tumor cells forms a reverse concentration gradient through moncarboxylate transporters (MCTs), forcing T cells to switch from lactate efflux to lactate influx [28]. This metabolic inversion leads to the accumulation of lactic acid and protons in T cells. Intracellular lactic acid can damage glycolysis, block the energy metabolism of T cells, thereby reducing the secretion of pro-inflammatory cytokines and ultimately causing T cell dysfunction [29].

The TME promotes the recruitment, differentiation and activity of Treg, and Treg maintain a high inhibitory function in the TME, constituting an obstacle to cancer immunity [30]. It is worth noting that the phenomenon mentioned above is limited to activated cytotoxic T cells, because the metabolic regulation of Treg is different. Effector T cells are more glucose-dependent, whereas Treg are less glucose-dependent [30]. Indeed, Treg thrive in a glucose-restricted environment, whereas Treg exposed to high glucose have reduced suppressive capacity. Recent studies have shown that the inhibitory function and proliferation of Treg are resistant to lactic acid at tumor-equivalent concentrations. Further, more than just resistance, Treg can take up lactic acid and show signs of activation and low glucose uptake. Treg do not require lactate for survival but have the metabolic flexibility to utilize this carbon source, both as fuel and as a way of protecting their high inhibitory capacity from the negative effects of glucose [31]. It is the unique metabolic mode of Treg that makes it used in the tumor microenvironment, leading to the prosperity and growth of suppressor cells in the microenvironment, and then promoting the occurrence of T cell exhaustion in the microenvironment.

2.1.2. Mechanism of the promoting effect of aerobic glycolysis on lytic bone damage

First, lactate produced by glycolysis has a lytic effect on hydroxyapatite in bone, causing it to release phosphate and calcium into the extracellular fluid [32]. In addition, osteoclast is the main cause of dissolving osseous lesions. Metabolic remodeling in the tumor microenvironment synergically drives osteoclast activation through tissue acidosis and lactic acid accumulation, and its mechanism of action is reflected in two interrelated levels. First, excess protons produced by cancer cell glycolysis lead to persistent acidosis in the extracellular microenvironment [33]. For osteoclasts, this acidified environment is a prerequisite for their successful activation [34]. Acidification conditions induce a transient increase in cytoplasmic free Ca²⁺ concentration, which triggers a calcium-dependent signaling cascade by activating the proton-sensing pathway in osteoclast precursor cells, prompting the nuclear translocation of the key transcription factor NFATc1, thereby initiating the osteoclast differentiation program and enhancing the expression of bone resorption-related genes [35]. Secondly, tumor-derived lactic acid is efficiently ingested by osteoclast precursor cells through MCT1 [36]. Due to the tumor consumption of glucose and high lactate production, other cells in the bone microenvironment, including osteoclasts, can only rely on low levels of glucose and high levels of extracellular lactate. Low levels of glucose are not a good thing for osteoclast activation, as glucose is the most potent energy substrate to support bone resorption [37,38], and both too low and too high glucose concentrations exert inhibitory effects on osteoclasts [39,40]. However, in this environment, osteoclasts were able to take up exogenous lactic acid and obtain more bioenergy by providing energy for mitochondrial metabolism [36]. It is due to the uptake of lactate that the differentiation process of osteoclasts is not affected [36]. Therefore, the acidosis of tumor-related tissues and the increase of extracellular lactic acid level together constitute the driving force to promote osteoclast differentiation and functional activation.

2.2. Dual effects of glutamine metabolism

2.2.1. Mechanism of glutamine depletion inhibiting T cell function

Glutamine, as a conditionally essential amino acid, plays a key role in the metabolic regulatory network of the TME [41]. It has been shown that activated T cells are dependent on glucose and glutamine to maintain cellular metabolism. Specifically, glutamine and α-ketoglutarate(α-KG) produced through the breakdown of glutaminase(GLS) and glutamine can play a key role in maintaining TCA intermediate levels [42]. Meanwhile, the level of interferon-γ (IFNγ) secretion by CD8⁺ T lymphocytes during malignant tumor progression is dependent on available glutamine and glutaminase activity, suggesting that CD8⁺ T cell-based immunotherapy strategies similarly depend on effective activation of glutamine metabolic pathways [43]. This finding reveals an important metabolic paradox in tumor immunity: both tumor cells and CD8⁺ T cells exhibit features of glutamine dependence (Fig. 3).

Fig. 3.

Dual effects of glutamine metabolism. Glutamine metabolism has a dual effect in the microenvironment of bone tumors. Tumor cells take up a large amount of glutamine, resulting in the depletion of glutamine in the microenvironment. This state of glutamine deficiency directly inhibits the activation and proliferation of T cells. Treg exhibits unique metabolic flexibility in an environment deficient in glutamine. They can differentiate normally and utilize lactic acid as an alternative energy source, thereby maintaining their high inhibitory function. In terms of bone repair, the deficiency of glutamine can reduce the differentiation of SSCs into osteoblast cell lines, resulting in a decrease in bone matrix mineralization. Glutamine also plays an important role in maintaining the redox balance of osteoblasts. It neutralizes excessive ROS by converting into glutathione, protecting osteoblasts from oxidative damage.

By Figdraw.

The function of T cells is strictly dependent on the supply of exogenous high-concentration glutamine. Even a moderate downregulation within the physiological concentration range can significantly inhibit their function. If the concentration continues to decrease, glutamine starvation of T cells significantly hinders T cell proliferation and cytokine production [44,45]. Moreover, other amino acids, including precursor molecules directly involved in biosynthetic pathways, are unable to compensate for the functional deficits caused by glutamine deficiency [44]. This illustrates the importance of glutamine metabolism for T cell-mediated immune responses.

At the same time, it has been shown that selective inhibition of glutamine metabolism in tumor cells improves antitumor T lymphocyte activity [46]. A classic example is competition in glutamine metabolism in triple-negative breast cancer (TNBC). TNBCs consume more glutamine and less glucose than other breast cancer subtypes, and are more dependent on glutamine metabolism to maintain tumor cell survival and proliferation [47]. Studies have shown that TNBCs usually express high levels of SLC1A5 and GLS [48,49], which leads to competitive predation of glutamine by tumor cells in the TME, limiting glutamine uptake from the environment by tumor infiltrating T lymphocytes and ultimately affecting their anti-tumor immune responses. Targeting glutamine metabolism in tumors increases interstitial glutamine concentrations to close to physiological plasma levels in mouse models and leads to an increase in the overall activation and effector capacity of T lymphocytes [50]。The possible explanation is that activated CD8⁺T cells can upregulate acetate metabolism to accommodate glutamine blockade, whereas cancer cells lack this metabolic plasticity and are highly sensitive to glutamine blockade [46]。In response, Deanna N Edwards et al. proposed the hypothesis of "glutamine stealing," in which cancer cells deprive tumor-infiltrating lymphocytes of glutamine needed to impair anti-tumor immune responses. They also pointed out that specific reduction of glutamine metabolism in tumor cells may increase the availability of glutamine in the tumor microenvironment, improve the redox state and activation of T lymphocytes, and ultimately achieve the targeting of tumor cells while protecting the therapeutic effect of anti-tumor T cells [50]。

However, the metabolism of Treg has its own particularity. SLC1A5 is critical for mediating TCR-stimulated glutamine uptake by naive T cells because it is required for the activation of TCR-and CD28-stimulated mTORC1 signaling [51]. However, SLC1A5 is completely unnecessary for the generation of naive CD4⁺ T cells into Treg, which also allows Treg to differentiate normally in the absence of glutamine [51]. The intrinsic reason may be that mTORC1 is required for the generation of Th1 and Th17 cells, but not for the generation of Treg [52]. It has been confirmed that in clear cell renal cell carcinoma (ccRCC), glutamine depletion by tumor cells can lead to glutamine deficiency in the microenvironment, which limits glutamine metabolism in tumor-infiltrating macrophages and activates HIF1α to transcription IL-23 in macrophages [53,54]. IL-23 could directly promote the proliferation of Treg and the production of IL-10/TGFβ. These factors strongly inhibit T-cell activation and cytotoxicity [54].

In summary, tumor cells establish an efficient competitive glutamine uptake mechanism by significantly up-regulating the expression levels of glutamine transporters such as SLC1A5 and metabolic key enzymes such as GLS. This metabolic reprogramming results in a significant depletion state of glutamine within the TME. This competitive glutamine depletion mechanism led by tumor cells ultimately promotes the failure of anti-tumor immune responses and immune escape through direct and indirect inhibition of effector T cell activation.

2.2.2. Glutamine depletion is not conducive to bone repair

Skeletal stem cells (SSC) play an important role in maintaining bone health and homeostasis due to its constant supply of osteoblasts [55]. If SSC differentiation is misspecified or not maintained, it leads to reduced osteoblast formation and reduced bone mass. It has been found that glutamine consumption and GLS activity significantly increase during osteoblast differentiation [56]. In vitro, glutamine deprivation reduces SSC differentiation into the osteoblastic lineage, resulting in reduced matrix mineralization, but increases differentiation into the adipocyte lineage [56]. Given the depletion of glutamine in the tumor microenvironment, this metabolic environment is likely to reduce osteoblast differentiation, which is essential for osteogenesis and repair. Brown et al. showed that glutamine significantly improved the viability and glucose utilization of osteoblasts in human osteoblast-like cell lines and mouse calvarial osteoblasts, and increased the expression level of osteocalcin in mouse calvarial osteoblast cultures, which favored matrix mineralization [57].

In addition, the conversion of glutamine to glutathione is also important for counterbalancing the destruction of osteoblasts by ROS and maintaining the redox balance in osteoblasts [58]。Experiments have shown that if the periosteal cells are treated with hypoxia in advance of bone repair, they activate the HIF signaling pathway, coordinating glutamine and glucose metabolism to adapt to the limited supply of oxygen and nutrients: Glucose is used to meet bioenergetic requirements, while glutamine is converted to glutathione to maintain redox homeostasis, thereby enhancing the survival of periosteal cells under the stress of hypoxia and glucose deprivation [59]. In contrast to the metabolic pattern in which tumor cells direct glutamine to the TCA cycle and reduce carboxylation to support biosynthesis and proliferation [60], osteoprogenitor cells preferentially utilize glutamine to neutralize excess ROS via the glutathione synthesis pathway [59]. This difference in metabolic orientation reflects the functional differences of glutamine in bone regeneration and tumor progression. Therefore, metabolic reprogramming of tumor cells leading to competitive depletion of glutamine may disrupt the regulation of redox balance in the bone repair microenvironment, which in turn inhibits the regenerative process.

https://BioRender.com/ckbbppz

3. Interaction network between T cell exhaustion and bone repair imbalance

3.1. The exhaustion of T cells in tumors promotes the occurrence of osteolytic lesions

Experiments have shown that T lymphocytes in bone metastases are able to significantly promote osteoclast generation [61]. The bone metastasis microenvironment has a suppressive effect on T cell activation, and T cell functional inactivation may be attributed to the expansion of metabolically active MDSCs in the microenvironment, including PD-L1⁺ M-MDSCs that are capable of differentiating into osteoclasts and inhibiting T cell activation [62]. Suppressed T cells may contribute to bone destruction through multiple pathways. First, suppressed T cells sorted from bone metastases had higher proosteoclast gene expression, resulting in more TNF-α and RANKL production, which promoted osteoclast production. Second, the loss of expression of some anti-osteoclast genes in suppressed T cells may also contribute. In addition, dysregulation of different T cell subsets in tumors may also contribute to the promotion of bone destruction [61]. Notably, T cell activation is able to inhibit osteoclast formation [61]. Therefore, we propose that metabolic reprogramming therapy may interfere with the progression of bone metastasis through dual mechanisms: enhancing T cell-mediated tumor cell killing and maintaining bone matrix homeostasis by inhibiting osteoclast production (Fig. 4).

Fig. 4.

The interaction between bone damage and T cell exhaustion. This figure depicts the complex interaction network between bone injury and T cell exhaustion, revealing their vicious cycle in the bone tumor microenvironment. The figure first shows how T cell exhaustion contributes to the development of osteolytic lesions. Specifically, T cells could significantly promote the generation of osteoclasts in bone metastases. The inhibition of T cell function may lead to an increase in the expression of osteoclast promoting genes, thereby producing more tumor necrosis TNF-α and RANKL. At the same time, the loss of anti-osteoclast factors and the imbalance of T cell subsets will further promote bone damage. Bone injury is also able to further inhibit T cell function through a variety of mechanisms. Bone injury results in an abnormal release of growth factors stored in the bone matrix, such as TGF-β and IGF, and an increase in extracellular calcium concentration. These changes disrupt the calcium homeostasis required by T cells, leading to intracellular calcium overload, which in turn inhibits T cell activation and proliferation.

Created in BioRender. Guo, S. (2025) https://BioRender.com/ckbbppz.

3.2. The inhibition of T cell function by bone damage

The underlying mechanism of T cell function inhibition in the bone tumor microenvironment may be closely related to the imbalance of calcium homeostasis. Under physiological conditions, when TCR is activated, phospholipase Cγ (PLCγ) decomposes PIP₂ to generate IP₃, which binds to the IP₃ receptor (IP₃R) on endoplasmic reticulum (ER), leading to the release of Ca²⁺from the ER calcium reservoir. Stromal interaction molecule 1 (STIM1) and STIM2 sense the decrease in Ca²⁺ levels in the ER lumen, which subsequently activates ORAI1 protein at the plasma membrane (PM) and induces store-operated Ca²⁺ entry (SOCE) [63]. Since the volume of ER is estimated to be only 1 % of the volume of T cell cytoplasm, SOCE is thought to be the primary mechanism for providing the calcium required for T cell activation [64]. However, hypercalcemia induced by bone tumors through a variety of mechanisms may disrupt this balance [65]. Animal experiments have shown that the continuous influx of pathologically elevated extracellular calcium concentration through SOCE leads to intracellular calcium overload far beyond the physiological requirement level. This high intracellular calcium level may lead to the burst of ROS, thereby inhibiting the activation and proliferation of T cells [66].

In the bone microenvironment, there is a bidirectional interaction between tumor cells and osteoclasts. This interaction has been termed a "vicious cycle" that ultimately leads to osteolysis and tumor growth [67]. In this "vicious cycle", overactivation of osteoclasts leads to the abnormal release of a large number of bone matrix stored growth factors (including TGF-β, IGF, etc.) as well as the rise of extracellular calcium concentration [67,68]. These growth factors can promote the differentiation of osteogenic progenitor cells in the physiological state, but form a pathological microenvironment that promotes tumor growth and immunosuppression in the tumor microenvironment. In particular, continuous exposure to TGF-β may, through its proven molecular mechanism of inducing CD8⁺ T cell exhaustion, create key regulatory mechanisms leading to T cell failure in the bone tumor microenvironment [69]. As a key pleiotropic cytokine regulating cell growth, differentiation, apoptosis, and immune regulation, TGF-β plays an important role in maintaining immune homeostasis by coordinating T cell development, homeostasis, and tolerance, and maintaining Treg in peripheral tissues [70,71]. Studies have demonstrated a significant correlation between TGF-β signaling and CD8⁺ T cell exhaustion phenotype. Experimental evidence shows that long-term exposure to TGF-β1 combined with continuous TCR stimulation can successfully induce CD8⁺ T cell exhaustion models in vitro, and blockade of TGF-β signaling can reverse this dysfunctional state [72,73]. Therefore, under the pathological condition of bone tumors, the abnormal release pattern of growth factors in the bone matrix provides a possible explanation for the relationship between the bone damage and T cell exhaustion.

4. Conventional strategies and challenges of small-mole drugs targeting metabolic pathways

After clarifying the dual regulatory mechanisms of metabolic reprogramming in bone tumors on T cell exhaustion and bone destruction, targeted metabolic intervention strategies have become the key to breaking this cycle. In recent years, significant progress has been made in the development of drugs targeting metabolic pathways, but there are still many challenges. We discuss current treatment strategies, barriers, and future directions for research.

The development and application of drugs targeting tumor metabolic reprogramming have made remarkable progress, but complex challenges remain [74]. At present, only a few drugs have been approved for clinical treatment, and most of them are still in pre-clinical or clinical trials. Due to space limitation, we only briefly introduce some of the drug research progress related to the content of this paper.

A variety of drugs targeting key enzymes of glycolysis are in various stages of investigation. For example, STF-31, BAY-876 and KL-11743, which target glucose transporter (GLUT), have shown potential to inhibit tumor growth in cell or animal experiments [[75], [76], [77], [78]].For hexokinase (HK), agents such as 3-bromopyruvate (3BP) and 2-deoxyglucose (2-DG) are also under investigation [79,80]. Inhibitors targeting phosphofructokinase (PFK), such as PFK158, have entered phase I clinical trials, with preliminary results showing good tolerability and antitumor activity [81,82]. Lactate dehydrogenase (LDH) inhibitors such as FX11, NHI-Glc-2, and NCI-006 have also been shown to inhibit tumor growth in animal experiments [[83], [84], [85]]. Meanwhile, drugs targeting MCTs, such as AZD3965 and VB124, are also under investigation, among which AZD3965 has entered phase I clinical trials [[86], [87], [88]]. Collectively, these drugs are expected to provide new strategies for cancer treatment by inhibiting key enzymes or transporters in glycolysis.

Tumor therapies targeting glutamine metabolic pathways are also diverse and promising. First, inhibitors targeting key enzymes of glutamine metabolism, such as GLS inhibitors BPTES and CB-839, and glutamate dehydrogenase (GLUD) inhibitors epigallocatechin gallate (EGCG) and R162, can effectively block the pathway of tumor cells using glutamine for proliferation [[89], [90], [91], [92]]. Among them, CB-839 has entered clinical trials and has shown promising efficacy in combination with other agents [90]. Secondly, inhibition strategies against glutamine transporters are being explored, such as SLC1A5 inhibitor V-9302 and SLC6A14 inhibitor α-MT, which can reduce the uptake of glutamine by tumor cells and inhibit tumor growth [93,94]. Besides, therapeutic strategies targeting glutamine redox homeostasis are being investigated, such as the SLC7A11 inhibitor sulfasalazine, which inhibits the growth of TNBC [95].

While having broad prospects, the research and development of such drugs also faces several difficulties. First, the metabolic network of tumor cells is highly plastic, and single-pathway inhibition often triggers compensatory reprogramming [20]. We should also consider that metabolic dependence varies among cancer types and even among subsets within the same tumor [96]. Furthermore, the extensive expression of metabolic key targets (such as HK and GLS) in normal tissues makes it difficult for drugs to balance efficacy and toxicity [20]. Typical examples include the toxicity of the glycolytic inhibitor 2-DG, which interferes with energy supply [80]. A further complication is that, as we noted above, metabolic interventions often come with a "therapeutic paradox": Although inhibition of glycolysis may alleviate microenvironment acidosis and enhance T-cell function, excessive blockade may deprive effector T cells of needed glycolytic energy. Similarly, targeting glutamine metabolism may inhibit CD8⁺ T cell proliferation by reducing α- KG supply while limiting tumor growth.

Although there are still great challenges in the complexity and treatment of tumor metabolic reprogramming, the continuous decoding of its spatiotemporal dynamic regulatory mechanism and the continuous evolution of intervention strategies will promote metabolic targeted therapy from theoretical breakthrough to clinical practice [97,98] (Fig. 5).

Fig. 5.

Challenges and countermeasures. While traditional small molecule metabolic inhibitors have limitations, multifunctional nanomaterials can provide a window of opportunity to destroy MIBN in bone tumors. Traditional inhibitors face multiple challenges: (1) Metabolic plasticity: tumor cells rapidly activate compensatory pathways after inhibition of a single pathway, leading to treatment resistance. (2) Systemic toxicity: key metabolic targets (such as HK and GLS) are widely expressed in normal tissues, causing off-target effects and dose-limiting toxicity. Multifunctional nanomaterials offer solutions: (1) Precise targeting: Surface engineering enables tumor-specific drug delivery through EPR effect/active targeting with minimal normal tissue damage. (2) Multimodal integration: co-delivery of metabolic inhibitors, immunomodulatory agents (such as checkpoint blockers), and osteogenic agents simultaneously disrupt tumor metabolism, reverse T cell exhaustion, and promote bone repair. (3) Improvement of pharmacokinetics: the precise design of nanomaterials can overcome the shortcomings of existing drugs (such as low water solubility), allowing more drugs to enter the clinic. These capabilities make multifunctional nanomaterials a transformative tool for fully subverting MIBN. Created in BioRender. Guo, S. (2025) https://BioRender.com/6uulpmu.

5. Using multifunctional nanomaterials to modulate metabolism: synergy and precision medicine

Bone tumor therapy demands simultaneous control of malignant metabolism, immune dysfunction, and skeletal homeostasis within a highly heterogeneous microenvironment. Multifunctional nanomaterials provide a programmable platform to co-deliver pathway-specific metabolic modulators, immune-revitalizing cues, and osteogenic factors, while activating them spatiotemporally in response to tumor-specific stimuli [[99], [100], [101]]. By aligning targeting, responsiveness, and combinatorial payloads, these systems can attenuate glycolysis-lactate toxicity and glutamine addiction, relieve T cell exhaustion, and promote bone repair—thereby interrupting the MIBN that sustains disease progression. In this chapter, we first outline delivery principles (Section 5.1) and integration patterns of functional modules (Section 5.2), then highlight application paradigms that directly address MIBN (Section 5.3), and finally summarize translational prospects and safety considerations (Section 5.4).

5.1. Targeted delivery principles for multifunctional nanomaterials

Precise delivery is foundational to the safety and efficacy of metabolism-targeted interventions. Passive targeting leverages abnormal tumor vasculature and interstitial retention—classically described as the enhanced permeability and retention (EPR) effect—to increase intratumoral exposure while reducing systemic toxicity [102]. Active targeting augments this by decorating carriers with ligands (antibodies, peptides, small molecules) that bind overexpressed receptors/transporters on tumor or stromal cells, thereby concentrating antimetabolic agents where they are most effective [103]. Such precision delivery has been shown in animal experiments not only to increase the concentration of drugs at the tumor site and enhance the therapeutic effect, but also to significantly reduce the toxic side effects of drugs on normal tissues [104,105].

Multifunctional designs further integrate microenvironment-responsive activation (pH, enzymes, ROS, hypoxia) to couple arrival with on-site release or structural transformation, reducing off-target exposure and aligning drug action with metabolic demand. This is especially relevant to immune metabolism: while moderating glycolysis or glutamine flux can alleviate acidosis and nutrient competition, indiscriminate blockade risks impairing effector T cell energetics. Spatiotemporal control mitigates this “therapeutic paradox” by restricting exposure to tumor regions and timing activation to windows that favor antitumor immunity.

Finally, nanocarriers can improve pharmacokinetics/solubility of otherwise impractical agents (e.g., insoluble glutaminase inhibitors) and co-package complementary payloads to pre-empt compensatory metabolic rewiring. Together, these delivery principles—passive/active targeting, stimuli-responsiveness, and PK optimization—establish a mechanistic basis for the multifunctional platforms detailed in Sections 5.2–5.3.

5.2. Multimodal functional integration of multifunctional nanomaterials

Delivery determines where and when a platform can act. Building on that foundation, multifunctional nanomaterials integrate distinct functional modules so that metabolic intervention, immune regulation and bone repair can operate in a coordinated manner. In this review, “multifunctional” denotes combinations that include at least one effector module (metabolic, immune, osteogenic or energy-based/cytotoxic), supported by enabling modules (targeting, retention, stimuli responsiveness, spatiotemporal gating, pharmacokinetic optimization) and, where appropriate, diagnostic modules for imaging or sensing. The goal is not simply to stack components, but to couple them in ways that yield measurable gains across the MIBN.

Effector modules are selected to be complementary rather than redundant. Metabolic regulators (e.g., attenuating the glycolysis–lactate axis, constraining glutamine dependence or rebalancing redox) can relieve acidosis and substrate competition that suppress antitumor immunity; immune effectors (ICD inducers, adjuvants, checkpoint or myeloid modulators) then convert this relieved niche into productive responses; osteogenic cues and antiresorptive actions counteract osteolysis and support structural recovery. Energy-based or cytotoxic modalities (PTT/PDT/SDT/RT or chemotherapy) are used not as stand-alone endpoints but to amplify metabolic vulnerabilities or to introduce controllable temporal windows for action.

5.3. Applications of multifunctional nanomaterials addressing the MIBN

In recent years, nanomaterial-based strategies for bone tumors have shifted from single-function constructs to integrated platforms capable of addressing multiple pathological processes in parallel. This evolution in design has produced distinct patterns in how therapeutic functions are combined, reflecting different priorities in modulating the tumor microenvironment and its systemic effects.

In this context, nanoplatforms can be broadly grouped by the functional combinations they incorporate, spanning dual-function designs to more comprehensive systems that unite several therapeutic objectives within a single construct. This perspective provides a coherent basis for examining representative examples and appreciating the range of design possibilities explored to date (Table 1).

Table 1.

Multifunctional nanomaterials for MIBN disruption.

Strategy Type	Nanoplatform	Targeted Pathways/Functions	Tumor Type	Reference
Metabolism + Bone repair	PLLA/nHA/MET	Warburg effect inhibition, osteogenic stimulation	Osteosarcoma	Tan et al. [106]
	Fe3O4/GOx/MgCO3@PLGA	Glucose depletion, magneto-thermal effects, osteogenesis	Residual bone tumor	Yu et al. [107]
Metabolism + Immunotherapy	CaCO3@PDA + Ce6 + SHK	pH buffering, ROS induction, immune cell activation	Osteosarcoma	Gao et al. [108]
	D/E@PM (DON + Etomoxir)	Glutamine and FAO inhibition; immune reprogramming	Colon cancer	Wang et al. [109]
Immunotherapy + Bone repair	αPD-L1 + Vismodegib + Mg2+	Checkpoint blockade, stem cell inhibition, osteogenesis	Osteosarcoma	Chu et al. [110]
Function module + Enabling module	DSS6-PEG-PLGA (As-Mn Nanocrystal)	Osteogenic niche-targeted, pH-responsive	Breast cancer bone metastasis	Liu et al. [111]
	DTX@AHP	Bone/tumor dual targeting, TME-triggered DTX release	Lung cancer bone metastasis	Bai et al. [112]

5.3.1. Coupling of metabolic targeting and osteogenic stimulation

One representative strategy involves the construction of a composite scaffold based on poly(L-lactic acid) (PLLA), nano-hydroxyapatite (nHA), and metformin (MET), which integrates mechanical support, bioactivity, and metabolic intervention. PLLA provides mechanical strength and biodegradability; nHA offers a bone-mimetic matrix to support adhesion and osteogenic differentiation of osteoblasts [106]. MET, beyond interfering with the Warburg effect to suppress glycolytic metabolism and proliferation of osteosarcoma cells, also promotes osteogenic differentiation, thus exerting a pro-regenerative effect. The incorporation of MET into the porous structure enables sustained release, prolonging its local anti-tumor activity. In vitro, this scaffold promoted osteogenic differentiation of bone mesenchymal stem cells (BMSCs), while inducing apoptosis and suppressing proliferation in osteosarcoma cells.

Another study focused on synergizing metabolic disruption and bone regeneration via a magnetothermal–starvation hybrid hydrogel system [107]. This system comprises Fe₃O₄ nanoparticles, glucose oxidase (GOx), and MgCO₃, embedded within an injectable PLGA-based hydrogel. Upon exposure to an alternating magnetic field, Fe₃O₄ generates mild hyperthermia for magnetothermal therapy; GOx efficiently depletes glucose, lowering ATP levels in tumor cells and weakening their heat shock response, thus sensitizing them to thermal damage; MgCO₃ serves as an inorganic reservoir for sustained release of Mg²⁺, supporting the local osteogenic microenvironment. In an orthotopic osteosarcoma model, this system significantly reduced tumor volume, demonstrating a synergistic anti-tumor effect.

These composite strategies illustrate the potential to simultaneously achieve energy metabolism disruption and bone regeneration within a single material platform, offering a viable dual-functional solution for post-surgical local treatment of bone tumors.

5.3.2. Integration of metabolic modulation and immune regulation

One design utilizes calcium carbonate/polydopamine nanoparticles (CaCO₃@PDA) as a core carrier, co-loading the photosensitizer Ce6 and the natural product shikonin(SHK) [108]. This system takes advantage of the pH-responsive nature of CaCO₃, which gradually releases alkaline ions in the acidic tumor microenvironment to neutralize local acidosis and thereby mitigate lactate-induced immunosuppression. SHK is capable of promoting immune cell activation and inducing ICD in tumor cells, while Ce6 generates ROS under light exposure, enabling PDT. The combination of Ce6 and SHK produces strong local ICD signals, leading to tumor antigen release and CD8⁺ T-cell activation. In an osteosarcoma model, this platform not only significantly suppressed tumor volume but also induced a higher proportion of infiltrating effector T cells and reduced Treg levels within the tumor tissue, suggesting a synergistic effect between metabolic relief and immune remodeling.

Another design strategy targets the metabolic dependencies of both tumor cells and immune cells [109]. A biomimetic nanoplatform (D/E@PM) was developed by encapsulating the glutamine antagonist DON and the fatty acid oxidation inhibitor etomoxir within nanoparticles cloaked in macrophage-derived membrane vesicles. After passive and active accumulation at the tumor site (colon cancer model), this system exerted dual effects: in tumor cells, DON inhibited glutaminolysis and glycolysis, while etomoxir suppressed fatty acid oxidation, jointly disrupting essential energy sources and thereby suppressing tumor growth; in immune cells, DON forced T cells to switch to alternative metabolic pathways (e.g., acetate utilization), enhancing CD8⁺ T-cell functionality, while etomoxir reprogrammed tumor-associated macrophages (TAMs) from an immunosuppressive M2 phenotype to a proinflammatory M1 phenotype. The combined therapy thus simultaneously disrupted tumor metabolism and boosted anti-tumor immunity, resulting in tumor growth inhibition, increased effector T-cell infiltration, and M1-polarized TAMs—hallmarks of immunologically mediated tumor clearance.

These approaches demonstrate the capacity of nanomaterials to integrate dual pathological targets. By modulating lactate and its downstream microenvironmental effects, such platforms not only attenuate tumor immune evasion mechanisms but also create more favorable metabolic conditions for effector immune cells.

5.3.3. Synergistic immunotherapy and bone regeneration

Preserving bone regeneration capacity while eradicating residual tumor cells imposes higher demands on material systems. By integrating immune checkpoint blockade and osteogenic microenvironment modulation within a single platform, certain designs have achieved dual regulation along the immune–bone axis.

Chu et al. developed an injectable hydrogel system that co-delivers an anti-PD-L1 antibody, the Hedgehog pathway inhibitor vismodegib, and a sustained-release source of Mg²⁺. This platform enables localized, sustained release of αPD-L1 at the post-surgical tumor margin to block immune escape signaling, while vismodegib selectively eliminates tumor stem-like cells to enhance immune-mediated clearance [110]. Simultaneously, the release of Mg²⁺ effectively promotes osteogenic differentiation and activity of BMSCs, upregulating osteogenesis-related gene expression and facilitating bone regeneration at the defect site. In vivo studies showed that mice treated with this hydrogel exhibited superior control of tumor recurrence, enhanced bone repair, and extended overall survival compared to controls.

This “elimination + regeneration” strategy provides a prolonged therapeutic window for comprehensive postoperative intervention. It bridges immune modulation and bone tissue repair within the MIBN framework, highlighting the therapeutic synergy between immune activation and osteogenesis.

5.3.4. Precision targeting and TME-responsive enabling

The TME exhibits high heterogeneity, with dynamic variations in metabolic states, pH, enzyme levels, and signaling pathways across different regions. Therefore, achieving precise spatial and temporal control over drug delivery is key to improving treatment selectivity.

To ensure that functional modules exert their effects at bone tumor sites, enabling mechanisms such as bone-targeting or microenvironment-responsive modules are often incorporated to enhance delivery efficiency and spatiotemporal precision. For example, Liu et al. modified the surface of PEG–PLGA nanoparticles with the DSS6 peptide, which targets the bone-forming niche, enabling the nanomedicine to accumulate at osteogenic sites within bone tissue [111]. These nanoparticles encapsulated arsenic–manganese nanocrystals as inhibitors of tumor colonization and were designed to release arsenic ions in response to acidic microenvironments. In a mouse model of breast cancer bone metastasis, this bone marrow–targeting nanomedicine significantly inhibited the adhesion and colonization of circulating tumor cells within the bone marrow, reduced the survival of dormant tumor cells, and ultimately prolonged the survival of the tumor-bearing mice. This study demonstrated that enabling designs such as bone-targeting peptides and acid-responsive release can significantly enhance the efficacy of anti-metabolic therapy in the bone metastatic setting.

Bai et al. reported a strategy that improves therapeutic efficacy by combining bone-affinitive and tumor-targeting moieties within one nanocarrier [112]. They constructed DTX@AHP nanoparticles by grafting alendronate and hyaluronic acid onto a dendritic PAMAM scaffold, enabling dual targeting of bone mineral and tumor cells, respectively, and loaded the particles with the chemotherapeutic agent docetaxel (DTX). These nanoparticles were designed to release DTX in response to the acidic and reductive conditions of the tumor microenvironment. In a co-culture model, DTX@AHP simultaneously inhibited osteoclast differentiation and tumor cell proliferation. In a mouse model of lung cancer bone metastasis, DTX@AHP selectively accumulated at bone lesions and achieved controlled drug release, effectively suppressing tumor growth and reducing bone destruction. This strategy highlights the therapeutic advantages of integrating functional modules with enabling mechanisms.

5.4. The clinical transformation potential and obstacles of nanomaterials

Although nanomaterials have shown great potential in the treatment of bone tumors, their clinical transformation still faces some challenges. First of all, the biosafety of nanomaterials is an important issue. So far, it is still very difficult to assess the in vivo and long-term toxicity of nanomaterials [113]. Nanomaterials themselves may have toxic effects on normal tissues. Secondly, the preparation process of nanomaterials is complex, making it difficult to achieve large-scale production and quality control. This limits the clinical application and promotion of nanomaterials [113]. Finally, the pharmacokinetic and pharmacodynamic behaviors of nanomaterials in vivo are not yet fully understood and require further in-depth studies [114]. But, some advantages demonstrated by nanomaterials in clinical transformation cannot be ignored. In the future, through interdisciplinary cooperation and innovation, it is expected to overcome the obstacles in the clinical transformation of nanomaterials, promote their wide application in the treatment of bone tumors, and achieve the integrated treatment of anti-cancer and bone repair targeting metabolic pathways.

6. Summary

This review delineates a self-perpetuating vicious cycle in bone tumors driven by tumor metabolic reprogramming. Dysregulated aerobic glycolysis and glutamine addiction induce microenvironmental acidosis and nutrient depletion, simultaneously promoting T cell exhaustion (via impaired glycolytic metabolism, lactate toxicity, and glutamine competition) and bone repair failure (through osteoclast activation and osteoblast suppression). Crucially, these pathologies reciprocally reinforce each other: Bone damage releases immunosuppressive factors (TGF-β, calcium) that further impair T cell function, while exhausted T cells exacerbate osteolysis through upregulated pro-osteoclast gene expression. This triad constitutes the Metabolic-Immune-Bone Network (MIBN), positioning tumor metabolism as the central driver of pathological progression.

Multifunctional nanomaterials emerge as a transformative strategy to disrupt the MIBN cycle. Their unique capacity for precision metabolic targeting (e.g., lactate degradation, glutaminase inhibition), multimodal functional integration, and microenvironmental modulation enables simultaneous anti-tumor and osteogenic functionality. By selectively disrupting tumor metabolic pathways while sparing effector T cells and promoting bone regeneration, nanomaterials overcome key limitations of conventional metabolic inhibitors. However, current research remains constrained by: (1) insufficient exploration of non-glycolytic metabolic axes (e.g., fatty acid/amino acid crosstalk) [115], (2) scarcity of clinical trial data validating nanomaterial safety/efficacy, and (3) incomplete molecular dissection of MIBN signaling pathways.

Future advancements must address these gaps through decoding fine-grained MIBN crosstalk, advancing stimuli-responsive nanomaterials for spatiotemporal metabolic control, and accelerating clinical translation via toxicity-mitigated designs. This integrated approach will validate the paradigm shift from “lesion clearance” to “holistic rehabilitation”, positioning nanomaterials as pivotal tools for breaking the metabolic-driven vicious cycle in bone oncology and improving patient outcomes. These processes together embody the 3R principle—remodel, repair, and remove—as an integrated framework for durable therapy.

CRediT authorship contribution statement

Shijin Guo: Writing – review & editing, Writing – original draft, Visualization. Ziyi Yan: Writing – review & editing, Visualization, Software. Yuling Huang: Writing – review & editing, Writing – original draft, Visualization. Xueneng Hu: Software, Resources. Huaiyuan Zhang: Validation, Project administration. Yu Wang: Visualization, Methodology, Investigation. Tinglin Zhang: Supervision, Methodology, Investigation. Huifen Qiang: Resources. Minghao Xue: Methodology, Investigation. Jie Gao: Validation, Supervision, Project administration, Conceptualization. Zuochong Yu: Supervision, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zuochong Yu reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.