The rapid growth of tumors relies heavily on a continuous supply of essential nutrients, including glucose and copper. Disrupting the nutrient supply to tumors has become an increasingly focal point in tumor therapy. However, solely blocking the energy supply typically only hinders further tumor growth and may not effectively eliminate existing tumor cells. Herein, a multifunctional cascade nanoreactor (HPP/TPEN@GC) endowed with N, N, N', N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN, a copper chelator) and glucose oxidase (GOx) is designed to disrupt both glycolysis and mitochondrial metabolism, which further induce cascade chemodynamic therapy (CDT). HPP/TPEN@GC can react with endogenous copper and glucose, thereby reducing their availability. The absence of copper prevents proper assembly and function of mitochondrial complex IV (CIV), hindering mitochondrial metabolism; the lack of glucose cuts off glycolysis and leads to a tumor specific starvation. Meanwhile, the reactions catalyzed by HPP/TPEN@GC contribute to the generation of Fenton-like catalysts and hydrogen peroxide (H2O2), which can further react to produce highly toxic hydroxyl radical (·OH) for CDT. Taken together, the multifunctional cascade nanoreactor reduces the availability of endogenous copper and glucose, and further takes advantage of them to generate ·OH for cascade starvation-chemodynamic therapy. Collectively, this work represents a distinctive therapeutic paradigm to harness endogenous copper and glucose, which should inspire further studies to take full advantage of endogenous nutrients to combat various diseases, including tumors.

Engineered enzymes with enhanced or novel functions are specific catalysts with wide-ranging applications in industry and medicine. Here, we introduce droplet array microfluidic enzyme kinetics (DA-MEK), a high-throughput enzyme screening platform that combines water-in-air droplet microarrays formed on patterned superhydrophilic/omniphobic surfaces with cell-free protein synthesis to enable cost-effective expression and quantitative kinetic characterization of enzyme variants. By printing DNA templates encoding enzyme variants onto hydrophilic spots, stamping slides to add cell-free expression mix, and imaging the resulting arrays, we demonstrate reproducible expression of enzyme variants across hundreds of microwells per slide, with line of sight toward replicating this across larger libraries. By specifically patterning slides with antibodies, we further demonstrate parallel immobilization, purification, and iterative characterization of the expressed variants. Subsequent stamping of fluorogenic substrates and time-lapse imaging allows determination of Michaelis-Menten parameters for each variant, with measured catalytic efficiencies spanning 5 orders of magnitude and agreeing well with values obtained via traditional microtiter plate assays. DA-MEK consumes orders of magnitude less reagents than plate-based assays, while providing accurate and detailed kinetic information for both beneficial and deleterious mutations. In future work, we anticipate that DA-MEK will provide a powerful and versatile platform to accelerate enzyme engineering and enable screening of large variant libraries under diverse conditions.

Metal sulfide nanomaterials (MeSNs) are highly promising for biomedical applications due to their low toxicity, good dispersibility, high stability, adjustable particle sizes, and good biocompatibility. Their unique chemical and light-conversion properties also enable them to function as photothermal or photodynamic agents, enhancing chemodynamic therapy (CDT) of tumors. This makes MeSNs valuable as photo-enhanced CDT nanoagents, advancing precision and multi-modal tumor treatment. This review examines recent advancements in MeSNs for photo-enhanced chemodynamic tumor ablation, comparing their effectiveness in CDT. It highlights the roles of photothermal, photodynamic, and photocatalytic effects in enhancing treatment efficacy. MeSN-based nanoreactors are categorized by composition into iron sulfide, copper sulfide, other unary, and multi-MeSNs for their applications in tumor therapy. Additionally, this review discusses challenges, limitations, and future biomedical applications of MeSNs, offering insights into their potential for next-generation cancer treatments.

Glucose metabolism reprogramming provides significant insights into the development and progression of malignant tumors. This study aims to explore the temporal-spatial evolution of the glucose metabolism in HCC using single-cell sequencing and spatial transcriptomics (ST), and validates G6PD as a potential therapeutic target for HCC.

We collected single-cell sequencing data from 7 HCC and adjacent non-cancerous tissues from the GSE149614 database, and ST data from 4 HCC tissues from the HRA000437 database. Pseudotime analysis was performed on the single-cell data, while ST data was used to analyze spatial metabolic activity. High-throughput sequencing and experiments, including wound healing, CCK-8, and transwell assays, were conducted to validate the role and regulatory mechanisms of G6PD in HCC.

Our study identified a progressive upregulation of PPP-related genes during tumorigenesis. ST analysis revealed elevated PPP metabolic scores in the central and intermediate tumor regions compared to the peripheral zones. High-throughput sequencing and experimental validation further suggested that G6PD-mediated regulation of HCC cell proliferation, migration, and invasion is likely associated with glutathione metabolism and ROS production. Finally, Cox regression analysis cofirmed G6PD as an independent prognostic factor for overall survival in HCC patients.

Our study provides novel insights into the changes in glucose metabolism in HCC from both temporal and spatial perspectives. We experimentally demonstrated that G6PD regulates proliferation, migration, and invasion in HCC and propose G6PD as a prognostic marker and therapeutic metabolic target for the HCC.

Developing advanced and effective enzyme-drug systems for cancer treatment is of significant interest. Herein, a novel approach is reported to create a highly active and robust enzyme-drug system. Glucose oxidase nanogels (nGOx) are first synthesized by polymerization on the surface of GOx using vinylimidazole as comonomers. Fe3+ are utilized to induce self-assembly of nGOx through the imidazole-metal coordination interaction to form GOx nanogel clusters (Fe@nGOx), enhancing the permeability and retention of nGOx into tumor cells by EPR effect. nGOx can deplete glucose in the presence of oxygen and generate H2O2, which is converted to highly cytotoxic hydroxyl radical (·OH) by Fe3+ and GSH, and the proximity between Fe3+ and GOx act in tandem for enhanced tumor therapy. The FeIII/FeII redox cycle reacts with GSH and H2O2, enabling continuous generation of ·OH within tumor cells, thus facilitating the anticancer effect. Moreover, the generation of H2O2 and ·OH can further promote the repolarization of tumor-associated macrophages from an M2 phenotype towards an M1 phenotype polarization, thus enhancing immune response. The cascade reaction between GOx and Fe3+/Fe2+ endows Fe@nGOx with excellent anti-tumor efficacy in mice models, highlighting its potential as a promising anticancer drug for clinical applications. This work establishes a new platform for utilizing enzyme/protein and metal ion complexes in versatile applications, advancing the field of enzyme-based cancer therapies.

Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability to induce oxidative stress and cuproptosis in cancer cells. However, their antitumor effectiveness is constrained by the dynamic redox balance and the metabolic shift between oxidative phosphorylation and glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) is designed for combined pyroptosis-cuproptosis cancer immunotherapy by amplifying reactive oxygen species (ROS) production and regulating cellular metabolism. The intracellular redox imbalance is achieved through the synergistic effects of α-KG-induced mitochondrial metabolic reprogramming, photothermally enhanced superoxide dismutase-like activity of polydopamine, and glutathione depletion by copper ions. The multifaceted redox modulation results in a substantial increase in intracellular ROS levels, triggering oxidative stress and subsequent pyroptosis in cancer cells. Furthermore, α-KG shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby enhancing cuproptosis induced by copper ions. The combination of ROS dyshomeostasis and glycolysis inhibition results in a potent enhancement of pyroptosis-cuproptosis-mediated cancer therapy. In a murine model of colorectal cancer, CKPP exhibited a remarkable anticancer effect, achieving a tumor inhibition rate of 96.3% and complete tumor eradication in two out of five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates significant potential for treating cancer through combined pyroptosis-cuproptosis cancer immunotherapy.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Metabolic reprogramming is a crucial characteristic of cancer, allowing cancer cells to acquire metabolic properties that support their survival, immune evasion, and uncontrolled proliferation. Consequently, targeting cancer metabolism has become an essential therapeutic strategy. Abnormal amino acid metabolism is not only a key aspect of metabolic reprogramming but also plays a significant role in chemotherapy resistance and immune evasion, particularly in leukemia. Changes in amino acid metabolism in tumor cells are typically driven by a combination of signaling pathways and transcription factors. Current approaches to targeting amino acid metabolism in leukemia include inhibiting amino acid transporters, blocking amino acid biosynthesis, and depleting specific amino acids to induce apoptosis in leukemic cells. Different types of leukemic cells rely on the exogenous supply of specific amino acids, such as asparagine, glutamine, arginine, and tryptophan. Therefore, disrupting the supply of these amino acids may represent a vulnerability in leukemia. This review focuses on the pivotal role of amino acids in leukemia metabolism, their impact on leukemic stem cells, and their therapeutic potential.

Catalytic nanoparticles (CNPs) as heterogeneous catalyst reveals superior activity due to their physio-chemical features, such as high surface-to-volume ratio and unique optical, electric, and magnetic properties. The CNPs, based on their physio-chemical nature, can either increase the reactive oxygen species (ROS) level for tumor and antibacterial therapy or eliminate the ROS for cytoprotection, anti-inflammation, and anti-aging. In addition, the catalytic activity of nanozymes can specifically trigger a specific reaction accompanied by the optical feature change, presenting the feasibility of biosensor and bioimaging applications. Undoubtedly, CNPs play a pivotal role in pushing the evolution of technologies in medical and clinical fields, and advanced strategies and nanomaterials rely on the input of chemical experts to develop. Herein, a systematic and comprehensive review of the challenges and recent development of CNPs for biomedical applications is presented from the viewpoint of advanced nanomaterial with unique catalytic activity and additional functions. Furthermore, the biosafety issue of applying biodegradable and non-biodegradable nanozymes and future perspectives are critically discussed to guide a promising direction in developing span-new nanozymes and more intelligent strategies for overcoming the current clinical limitations.

Danggui Buxue (DGBX) decoction is a classical prescription composed of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), used to enrich blood, and nourish Qi in Chinese medicine, with the potential to recover energy and stimulate metabolism. Chronic inflammation is a risk factor in the development of inflammatory bowel disease (IBD)-related colorectal cancer (CRC). More importantly, AR and ASR have anti-inflammatory and anti-cancer activities, as well as prefiguring a potential effect on inflammation-cancer transformation. We, therefore, aimed to review the immunometabolism potential of DGBX decoction and its components in this malignant transformation, to provide a helpful complement to manage the risk of IBD-CRC. The present study investigates the multifaceted roles of DGBX decoction and its entire components AR and ASR, including anti-inflammation effects, anti-cancer properties, immune regulation, and metabolic regulation. This assessment is informed by a synthesis of scholarly literature, with more than two hundred articles retrieved from PubMed, Web of Science, and Scopus databases within the past two decades. The search strategy employed utilized keywords such as "Danggui Buxue", "Astragali Radix", "Angelicae Sinensis Radix", "Inflammation", and "Metabolism", alongside the related synonyms, with a particular emphasis on high-quality research and studies yielding significant findings. The potential of DGBX decoction in modulating immunometabolism holds promise for the treatment of IBD-related CRC. It is particularly relevant given the heterogeneity of CRC and the growing trend towards personalized medicine, but the precise and detailed mechanism necessitate further in vivo validation and extensive clinical studies to substantiate the immunometabolic modulation and delineate the pathways involved.

Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC50 value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.

Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1Δ mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1Δ strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1Δ strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin ® A as a compound restoring growth on glucose of the yeast tps1Δ mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin ® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin ® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1Δ cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin ® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism.

Glycinamide ribonucleotide formyltransferase (GARFT) is an important enzyme in the folate metabolism pathway, and chemical drugs targeting GARFT have been used in tumor treatments over the past few decades. The development of novel antimetabolism drugs that target GARFT with improved performance and superior activity remains an attractive strategy. Herein, we proposed a targeted double-template molecularly imprinted polymer (MIP) for enhancing macrophage phagocytosis and synergistic antimetabolic therapy. The double-template MIP was prepared by imprinting the exposed peptide segment of the extracellular domain of CD47 and the active center of GARFT. Owing to the imprinted cavities on the surface of MIP, it can actively target cancer cells and mask the "do not eat me" signal upon binding to CD47 thereby blocking the CD47-SIRPα pathway and ultimately enhancing phagocytosis by macrophages. In addition, MIP can specifically bind to the active center of GARFT upon entry into the cells, thereby inhibiting its catalytic activity and ultimately interfering with the normal expression of DNA. A series of cell experiments demonstrated that MIP can effectively target CD47 overexpressed 4T1 cancer cells and inhibit the growth of 4T1 cells. The enhanced phagocytosis ability of macrophages-RAW264.7 cells was also clearly observed by confocal imaging experiments. In vivo experiments also showed that the MIP exhibited a satisfactory tumor inhibition effect. Therefore, this study provides a new idea for the application of molecular imprinting technology to antimetabolic therapy in conjunction with macrophage-mediated immunotherapy.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Development of biocompatible nanomaterials with mitochondria-targeting and multimodal therapeutic activities is important for cancer treatment. Herein, we designed and synthesized a multifunctional pyrrole-based nanomaterial with photothermal effects and mitochondria-targeting properties from polypyrrole and the pro-apoptotic peptide KLA. Different from traditional strategies for the preparation of PPy nanoparticles, we innovatively used the KLA peptide as the template and CuCl2 as the catalyst to trigger the oxidative polymerization of pyrrole for PPy-KLA-Cu nanoparticle formation. Besides, due to the presence of mixed-valence Cu(I)/Cu(II) states, PPy-KLA-Cu nanoparticles also exhibited multienzyme-like activities, such as peroxidase, ascorbate oxidase and glutathione peroxidase activities, which can be exploited to elevate the intracellular ROS level and simultaneously consume GSH in cancer cells. More importantly, the heat generated by PPy-KLA-Cu nanoparticles from NIR irradiation could enhance the nanozymatic activities for ROS elevation and increase the KLA-induced anticancer activity via mitochondrial dysfunction, realizing multimodal treatment of cancer cells with improved therapeutic efficacy.

Dexmedetomidine hydrochloride (DEX-HCl) and sufentanil citrate (SFC) are commonly used anesthetic drugs for esophageal cancer (EC) surgery. The present study was performed to investigate the effect of DEX-HCl and SFC treatment on glucose metabolism and epithelial-mesenchymal transition in EC. Cell counting kit-8 (CCK8), clonogenic, wound healing and Transwell migration assays were performed to assess the effects of the DEX-HCl and SFC on KYSE30 cell proliferation, invasion and migration. Changes in lactate and glucose levels in KYSE30 cells were also detected. Western blot analysis was used to determine the protein expression levels of the JAK/STAT signaling pathway and glucose metabolism-related proteins. The results of CCK8, clonogenic and wound healing assays demonstrated that DEX-HCl and SFC inhibited KYSE30 cell proliferation, invasion and migration. Similarly, the combined DEX-HCl and SFC treatment significantly reduced lactate production, ATP production and glucose levels in KYSE30 cells. Western blotting indicated that DEX-HCl and SFC could reduce JAK/STAT and metastasis-related protein expression. Demonstrating a reduction in Hexokinase 2, matrix metallopeptidase 2 and 9, N-cadherin and lactate dehydrogenase A protein expression levels. The effects of DEX-HCl and SFC combined treatment were counteracted by the addition of JAK/STAT pathway activator RO8191, which suggested that DEX-HCl and SFC could serve a role in mediating the JAK/STAT signaling pathway in KYSE30 cells.

Reprogramming of the serine synthesis pathway (SSP) is intricately linked to the progression of epithelial ovarian cancer (EOC). CBR-5884, a selective small-molecule inhibitor targeting phosphoglycerate dehydrogenase (PHGDH), effectively impedes the de novo synthesis of serine within cancer cells. This study aimed to evaluate the inhibitory effect of CBR-5884 on EOC cells and delineate its specific mechanism, thereby proposing a novel therapeutic approach for treating EOC. The suppression of serine biosynthesis after CBR-5884 treatment was evaluated using RNA sequencing and a serine assay kit, and the results showed that CBR-5884 effectively downregulated serine biosynthesis in EOC cells, particularly those expressing high levels of PHGDH. In vitro studies revealed that CBR-5884 demonstrated significant antitumor effects and suppressed migration and invasion of EOC cells through down-regulation of the integrin subunit beta 4 (ITGB4)/extracellular signal-regulated kinase (ERK)/epithelial-mesenchymal transition signal axis. Additionally, CBR-5884 mitigated the stemness of EOC cells and heightened their sensitivity to chemotherapy. Moreover, in vivo studies revealed that CBR-5884 significantly delayed tumor growth, with histological analysis indicating the safety profile of CBR-5884. Finally, the patient-derived organoid (PDO) models were utilized to explore the preclinical efficacy of CBR-5884 against EOC cells, and the results unveiled that CBR-5884 impeded proliferation and downregulated the expression of ITGB4 in EOC PDO models. Our findings supports the anticancer properties of CBR-5884 in EOC cells exhibiting high PHGDH expression, manifesting through the suppression of proliferation, migration, and invasion, while enhancing chemotherapy sensitivity, suggesting that CBR-5884 holds promise as an efficacious strategy for the treatment of EOC.

Accurate cellular-recognition based disease therapy is of significance for precision medicine. However, except of specific antibody-coupling strategy, very few probes have been reported to efficiently discriminate normal cells and lesion cells through cellular microenvironment. Herein, we proposed a glucose selectively-lightened upconversion nanoprobe to recognize cancer cells from a pile of normal cells based on Warburg effect, that indicated a heightened demand for glucose intake for cancer cells. The nanoprobes were constructed by mesoporous silica-coated upconversion nanoparticles (UCNP@mSiO2) with the crucial incorporation of a glucose-responsive modality, benzoboric acid (BA)-modified fluorescein molecules (FITC-BA). In cancer cells, the presence of elevated glucose concentrations triggered the transformation of FITC-BA to FITC-Glucose to recover nanoprobes' luminescence, however, the nanoprobes exhibited a shielded luminescent effect in healthy cells. To validate the hypothesis of accurate cellular-discrimination, a photodynamic therapy modality, riboflavin, with a specific ratio were also loaded into above UCNP@mSiO2 nanoprobes for effective production of reactive oxygen species to kill cells. It was found that 97.8% of cancer cells were cleaned up, but normal cells retained a nearly 100% viability after 10 min laser illumination. By leveraging the metabolic disparity from Warburg effect, the nanoprobes offer a highly accurate cellular discrimination, and significantly mitigate "off-target" damage commonly associated with conventional therapies.

Schiff bases attract research interest due to their applications in chemical synthesis and medicinal chemistry. In recent years, benitrobenrazide and benserazide containing imine moiety have been synthesized and characterized as promising inhibitors of hexokinase 2 (HK2), an enzyme overexpressed in most cancer cells. Benserazide and benitrobenrazide possess a common structural fragment, a 2,3,4-trihydroxybenzaldehyde moiety connected through a hydrazone or hydrazine linker acylated on an N' nitrogen atom by serine or a 4-nitrobenzoic acid fragment. To avoid the presence of a toxicophoric nitro group in the benitrobenrazide molecule, we introduced common pharmacophores such as 4-fluorophenyl or 4-aminophenyl substituents. Modification of benserazide requires the introduction of other endogenous amino acids instead of serine. Herein, we report the synthesis of benitrobenrazide and benserazide analogues and preliminary results of inhibitory activity against HK2 evoked by these structural changes. The derivatives contain a fluorine atom or amino group instead of a nitro group in BNB and exhibit the most potent inhibitory effects against HK2 at a concentration of 1 µM, with HK2 inhibition rates of 60% and 54%, respectively.

Lung adenocarcinoma (LUAD) is a malignant tumor with high lethality, and the aim of this study was to identify promising biomarkers for LUAD. Using the TCGA-LUAD dataset as a discovery cohort, a novel joint framework VAEjMLP based on variational autoencoder (VAE) and multilayer perceptron (MLP) was proposed. And the Shapley Additive Explanations (SHAP) method was introduced to evaluate the contribution of feature genes to the classification decision, which helped us to develop a biologically meaningful biomarker potential scoring algorithm. Nineteen potential biomarkers for LUAD were identified, which were involved in the regulation of immune and metabolic functions in LUAD. A prognostic risk model for LUAD was constructed by the biomarkers HLA-DRB1, SCGB1A1, and HLA-DRB5 screened by Cox regression analysis, dividing the patients into high-risk and low-risk groups. The prognostic risk model was validated with external datasets. The low-risk group was characterized by enrichment of immune pathways and higher immune infiltration compared to the high-risk group. While, the high-risk group was accompanied by an increase in metabolic pathway activity. There were significant differences between the high- and low-risk groups in metabolic reprogramming of aerobic glycolysis, amino acids, and lipids, as well as in angiogenic activity, epithelial-mesenchymal transition, tumorigenic cytokines, and inflammatory response. Furthermore, high-risk patients were more sensitive to Afatinib, Gefitinib, and Gemcitabine as predicted by the pRRophetic algorithm. This study provides prognostic signatures capable of revealing the immune and metabolic landscapes for LUAD, and may shed light on the identification of other cancer biomarkers.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 μM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.

Although hepatocellular carcinoma (HCC) is rather frequent, little is known about the molecular pathways underlying its development, progression, and prognosis. In the current study, we comprehensively analyzed the deferentially expressed metabolism-related genes (MRGs) in HCC based on TCGA datasets attempting to discover the potentially prognostic genes in HCC. The up-regulated MRGs were further subjected to analyze their prognostic values and protein expressions. Twenty-seven genes were identified because their high expressions were significant in OS, PFS, DFS, DSS, and HCC tumor samples. They were then used for GO, KEGG, methylation, genetics changes, immune infiltration analyses. Moreover, we established a prognostic model in HCC using univariate assays and LASSO regression based on these MRGs. Additionally, we also found that SLC38A1, an amino acid metabolism closely related transporter, was a potential prognostic gene in HCC, and its function in HCC was further studied using experiments. We found that the knockdown of SLC38A1 notably suppressed the growth and migration of HCC cells. Further studies revealed that SLC38A1 modulated the development of HCC cells by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism. In conclusion, this study identified the potentially prognostic MRGs in HCC and uncovered that SLC38A1 regulated HCC development and progression by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism, which might provide a novel marker and potential therapeutic target in HCC.

Due to the high mortality and incidence rates associated with tumors and the specificity of the tumor microenvironment (TME), it is difficult to achieve a complete cure for tumors using a single therapy. In this study, calcium carbonate-modified palladium hydride nanoparticles (PdH@CaCO3) were prepared and utilized for the combined treatment of tumors through chemodynamic therapy (CDT)/photothermal therapy (PTT) and calcium overload therapy. After entering tumor cells, PdH@CaCO3 releases calcium ions (Ca2+) and PdH once it reaches the TME due to the pH reactivity of the calcium carbonate coating. The mitochondrial membrane potential is lowered by the Ca2+, leading to irreversible cell damage. Meanwhile, PdH reacts with excessive hydrogen peroxide (H2O2) in the TME via the Fenton reaction, generating hydroxyl radicals (·OH). Moreover, PdH is an excellent photothermal agent that can kill tumor cells under laser irradiation, leading to significant anti-tumor effects. In vitro and in vivo studies have demonstrated that PdH@CaCO3 could combine CDT/PTT and calcium overload therapy, exhibiting great clinical potential in the treatment of tumors.

A novel Au-nucleic acid nanoprobe, catalyzed by mRNA, has been developed for live cell imaging and precise treatment of tumor cells. This nanoprobe exhibits the remarkable ability to differentiate between tumor cells and normal cells through live cell mRNA imaging, while selectively inducing apoptosis in tumor cells.

A novel photocaged PI3K inhibitor 2 was designed and synthesized by introducing a cascade photocaging group to block its key interaction with the kinase. Upon UV light irradiation, the photocaged compound released a highly potent PI3K inhibitor to recover its anticancer properties and a fluorescent dye for real-time reporting of drug release, providing a new approach for studying the PI3K signaling transduction pathway as well as developing precisely controlled cancer therapeutics.

High temperature generated by photothermal therapy (PTT) can trigger an inflammatory response at the tumor site, which not only limits the efficacy of PTT but also increases the risk of tumor metastasis and recurrence. In light of the current limitations posed by inflammation in PTT, several studies have revealed that inhibiting PTT-induced inflammation can significantly improve the efficacy of cancer treatment. In this review, we summarize the research progress made in combining anti-inflammatory strategies to enhance the effectiveness of PTT. The goal is to offer valuable insights for developing better-designed photothermal agents in clinical cancer therapy.

Exosomes are nanovesicles 40-120 nm in diameter secreted by almost all cell types and providing humoral intercellular interactions. Given the natural origin and high biocompatibility, the potential for loading various anticancer molecules and therapeutic nucleic acids inside, and the surface modification possibility for targeted delivery, exosomes are considered to be a promising means of delivery to cell cultures and experimental animal organisms. Milk is a unique natural source of exosomes available in semi-preparative and preparative quantities. Milk exosomes are highly resistant to the harsh conditions of the gastrointestinal tract. In vitro studies have demonstrated that milk exosomes have an affinity to epithelial cells, are digested by cells by endocytosis mechanism, and can be used for oral delivery. With milk exosome membranes containing hydrophilic and hydrophobic components, exosomes can be loaded with hydrophilic and lipophilic drugs. This review covers a number of scalable protocols for isolating and purifying exosomes from human, cow, and horse milk. Additionally, it considers passive and active methods for drug loading into exosomes, as well as methods for modifying and functionalizing the surface of milk exosomes with specific molecules for more efficient and specific delivery to target cells. In addition, the review considers various approaches to visualize exosomes and determine cellular localization and bio-distribution of loaded drug molecules in tissues. In conclusion, we outline new challenges for studying milk exosomes, a new generation of targeted delivery agents.

Hepatoblastoma (HB) is the most common malignant liver tumor among children. To gain insight into the pathobiology of HB, we performed RNA sequence analysis on 5 patient-derived xenograft lines (HB-243, HB-279, HB-282, HB-284, HB-295) and 1 immortalized cell line (HUH6). Using cultured hepatocytes as a control, we found 2,868 genes that were differentially expressed in all of the HB lines on mRNA level. The most upregulated genes were ODAM, TRIM71, and IGDCC3, and the most downregulated were SAA1, SAA2, and NNMT. Protein-protein interaction analysis identified ubiquitination as a key pathway dysregulated in HB. UBE2C, encoding an E2 ubiquitin ligase often overexpressed in cancer cells, was markedly upregulated in 5 of the 6 HB cell lines. Validation studies confirmed UBE2C immunostaining in 20 of 25 HB tumor specimens versus 1 of 6 normal liver samples. The silencing of UBE2C in two HB cell models resulted in decreased cell viability. RNA sequencing analysis showed alterations in cell cycle regulation after UBE2C knockdown. UBE2C expression in HB correlated with inferior patient survival. We conclude that UBE2C may hold prognostic utility in HB and that the ubiquitin pathway is a potential therapeutic target in this tumor.

Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts.

This paper describes the synthesis of a polymer-prodrug conjugate, its aqueous self-assembly, noncovalent encapsulation of a second drug, and stimuli-responsive intracellular dual drug delivery. Condensation polymerization between a functionalized diol and a commercially available diisocyanate in the presence of poly(ethylene glycol) hydroxide (PEG-OH) as the chain stopper produces an ABA-type amphiphilic block copolymer (PU-1) in one pot, with the middle hydrophobic block being a polyurethane containing a pendant tert-butyloxycarbonyl (Boc)-protected amine in every repeating unit. Deprotection of the Boc group, followed by covalent attachment of the Pt(IV) prodrug using the pendant amine groups, produces the polymer-prodrug conjugate PU-Pt-1, which aggregates to nanocapsule-like structures in water with a hydrophilic interior. In the presence of sodium ascorbate, the Pt(IV) prodrug can be detached from the polymer backbone, producing the active Pt(II) drug. Cell culture studies show appreciable cell viability by the parent polymer. However, the polymer-prodrug conjugate nanocapsules exhibit cellular uptake and intracellular release of the active drug under a reducing environment. The capsule-like aggregates of the polymer-prodrug conjugate were used for noncovalent encapsulation of a second drug, doxorubicin (Dox), and Dox-loaded PU-Pt-1 aggregate showed a significantly superior cell killing efficiency compared to either of the individual drugs, highlighting the promising application of such a dual-drug-delivery approach.

Aerobic glycolysis is a process that metabolizes glucose under aerobic conditions, finally producing pyruvate, lactic acid, and ATP for tumor cells. Nevertheless, the overall significance of glycolysis-related genes in colorectal cancer and how they affect the immune microenvironment have not been investigated.

By combining the transcriptome and single-cell analysis, we summarize the various expression patterns of glycolysis-related genes in colorectal cancer. Three glycolysis-associated clusters (GAC) were identified with distinct clinical, genomic, and tumor microenvironment (TME). By mapping GAC to single-cell RNA sequencing analysis (scRNA-seq), we next discovered that the immune infiltration profile of GACs was similar to that of bulk RNA sequencing analysis (bulk RNA-seq). In order to determine the kind of GAC for each sample, we developed the GAC predictor using markers of single cells and GACs that were most pertinent to clinical prognostic indications. Additionally, potential drugs for each GAC were discovered using different algorithms.

GAC1 was comparable to the immune-desert type, with a low mutation probability and a relatively general prognosis; GAC2 was more likely to be immune-inflamed/excluded, with more immunosuppressive cells and stromal components, which also carried the risk of the poorest prognosis; Similar to the immune-activated type, GAC3 had a high mutation rate, more active immune cells, and excellent therapeutic potential.

In conclusion, we combined transcriptome and single-cell data to identify new molecular subtypes using glycolysis-related genes in colorectal cancer based on machine-learning methods, which provided therapeutic direction for colorectal patients.

It is estimated that there are over 890,000 new cases of head and neck squamous cell carcinoma (HNSCC) worldwide each year, accounting for approximately 5% of all cancer cases. Current treatment options for HNSCC often cause significant side effects and functional impairments, thus there is a challenge to discover more acceptable treatment technologies. Extracellular vesicles (EVs) can be utilized for HNSCC treatment in several ways, for example, for drug delivery, immune modulation, as biomarkers for diagnostics, gene therapy, or tumor microenvironment modulation. This systematic review summarizes new knowledge regarding these options. Articles published up to 11 December 2022, were identified by searching the electronic databases PubMed/MEDLINE, Scopus, Web of Science, and Cochrane. Only full-text original research papers written in English were considered eligible for analysis. The quality of studies was assessed using the Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies, modified for the needs of this review. Of 436 identified records, 18 were eligible and included. It is important to note that the use of EVs as a treatment for HNSCC is still in the early stages of research, so we summarized information on challenges such as EV isolation, purification, and standardization of EV-based therapies in HNSCC.

Tumor microenvironment is characterized by the high concentration of reactive oxygen species (ROS), which is an effective key used to open the Pandora's Box against cancer. Herein, a tumor-targeted nanosystem HFNP@GOX@PFC composed of ROS-cleaved Fe-based metal-organic framework, hyaluronic acid (HA), glucose oxidase (GOX) and perfluorohexane (PFC) has been developed for tumor cascade amplified starvation and chemodynamic therapy (CDT). In response to the high concentration of hydrogen peroxide (H₂O₂) intratumorally, HFNP@GOX@PFC endocytosed by tumor cells can specially be disassembled and release GOX, PFC and Fe²⁺, which can collectively starve tumor and self-produce additional H₂O₂ via competitively glucose catalyzing, supply oxygen to continuous support GOX-mediated starvation therapy, initiate CDT and cascade amplify oxidative stress via Fe²⁺-mediated Fenton reaction, leading to the serious tumor damage with activated p53 signal pathway. Moreover, HFNP@GOX@PFC also significantly initiates antitumor immune response via re-educating tumor-associated macrophages (TAMs) by activating NF-κB and MAPK signal pathways. In vitro and in vivo results collectively demonstrate that nanosystem not only continuously initiates starvation therapy, but also pronouncedly cascade-amplify CDT and polarize TAMs, consequently efficiently inhibiting tumor growth with good biosafety. The functional nanosystem combined the cascade amplification of starvation and CDT provides a new nanoplatform for tumor therapy.

Manipulating Fenton chemistry in tumor microenvironment (TME) for the generation of reactive oxygen species is an effective strategy for chemodynamic therapy. However, this is usually restricted by limited intracellular content of H₂O₂ and insufficient acidic environment at the tumor site. Herein, a ferric metal-organic framework (MOF) is covalently grafted with a prodrug of cisplatin (Pt(IV) prodrug) and loaded with a biocatalyst glucose oxidase (GOx) to afford a nanozyme MOF-Pt(IV)@GOx for cascade reactions. In this system, the attached Pt(IV) prodrug on MOF plays a significant role in the cooperative enhancement of GOx loading and chemotherapy. The high concentration of glutathione in TME reduces Fe(III) to Fe(II) for Fenton reaction, and converts Pt(IV) prodrug to cisplatin for DNA targeting and H₂O₂ production. Meanwhile, glucose oxidation catalyzed by GOx not only consumes glucose for starvation therapy, but also promotes the intracellular acidity and H₂O₂ supply in TME, which are in favor of Fenton reaction. Both in vitro and in vivo studies demonstrate that MOF-Pt(IV)@GOx enables remarkable anticancer efficacy due to the synergistic trimodal therapy consisting of ferroptosis, starvation therapy, and chemotherapy.

The metabolome is the best representation of cancer phenotypes. Gene expression can be considered a confounding covariate affecting metabolite levels. Data integration across metabolomics and genomics to establish the biological relevance of cancer metabolism is challenging. This study aimed to eliminate the confounding effect of metabolic gene expression to reflect actual metabolite levels in microsatellite instability (MSI) cancers.

In this study, we propose a new strategy using covariate-adjusted tensor classification in high dimensions (CATCH) models to integrate metabolite and metabolic gene expression data to classify MSI and microsatellite stability (MSS) cancers. We used datasets from the Cancer Cell Line Encyclopedia (CCLE) phase II project and treated metabolomic data as tensor predictors and data on gene expression of metabolic enzymes as confounding covariates.

The CATCH model performed well, with high accuracy (0.82), sensitivity (0.66), specificity (0.88), precision (0.65), and F1 score (0.65). Seven metabolite features adjusted for metabolic gene expression, namely, 3-phosphoglycerate, 6-phosphogluconate, cholesterol ester, lysophosphatidylethanolamine (LPE), phosphatidylcholine, reduced glutathione, and sarcosine, were found in MSI cancers. Only one metabolite, Hippurate, was present in MSS cancers. The gene expression of phosphofructokinase 1 (PFKP), which is involved in the glycolytic pathway, was related to 3-phosphoglycerate. ALDH4A1 and GPT2 were associated with sarcosine. LPE was associated with the expression of CHPT1, which is involved in lipid metabolism. The glycolysis, nucleotide, glutamate, and lipid metabolic pathways were enriched in MSI cancers.

We propose an effective CATCH model for predicting MSI cancer status. By controlling the confounding effect of metabolic gene expression, we identified cancer metabolic biomarkers and therapeutic targets. In addition, we provided the possible biology and genetics of MSI cancer metabolism.

This work for the first time reports on a simple and rapid colorimetric immunoassay with rapid coordination of ascorbic acid 2-phosphate (AAP) and iron (III) for determination of carcinoembryonic antigen (CEA, used as a model) by using Fe₂O₃ nanoparticle based-chromogenic substrate system. The signal was produced rapidly (1 min) from the coordination of AAP and iron (III) with color development of colorless to brown. TD-DFT calculation methods were employed to simulate the UV-Vis spectra of AAP-Fe²⁺ and AAP-Fe³⁺ complexes. Moreover, Fe₂O₃ nanoparticle could be dissolved with the aid of acid, thereby releasing free iron (III). Herein, a sandwich-type immunoassay was established based on Fe₂O₃ nanoparticle as labels. As target CEA concentration increased, the number of Fe₂O₃ labelled-antibodies (bound specifically) increased, resulting in loading more Fe₂O₃ nanoparticle on platform. The absorbance increased as the number of free iron (III), derived from Fe₂O₃ nanoparticle, increased. So, the absorbance of reaction solution is positively correlated with antigen concentration. Under optimal conditions, the current results showed good performance for CEA detection in the range 0.02-10.0 ng/mL with a detection limit of 11 pg/mL. Moreover, the repeatability, stability, and selectivity of the colorimetric immunoassay were also acceptable.

Early nutritional treatment is crucial for the care of patients with operable and advanced gastrointestinal malignancies. Therefore, much research has focused on nutritional support for patients with gastrointestinal malignancies. Therefore, this study aimed to evaluate the global scientific output and activity with respect to nutritional support and gastrointestinal malignancy.

We searched in Scopus for publications on gastrointestinal cancer and nutritional assistance published between January 2002 and December 2021. Then, using VOSviewer 1.6.18 and Microsoft Excel 2013, we conducted bibliometric analysis and visualization.

A total of 906 documents were published between 2002 and 2021, including 740 original articles (81.68%) and 107 reviews (11.81%). China ranked first (298 publications, 32.89%), Japan ranked second (86 publications, 9.49%) and the USA ranked third (84 publications, 9.27%). The organisation with the highest number of publications was the Chinese Academy of Medical Sciences & Peking Union Medical College from China, with 14 articles, followed by the Peking Union Medical College Hospital from China and the Hospital Universitari Vall d'Hebron from Spain (13 publications for each). Before 2016, most studies focused on 'nutrition support for patients undergoing gastrointestinal surgery'. However, the latest trends showed that 'nutrition support and clinical outcomes in gastrointestinal malignancies' and 'malnutrition in patients with gastrointestinal cancer' would be more widespread in the future.

This review is the first bibliometric study to provide a thorough and scientific analysis of gastrointestinal cancer and nutritional support trends worldwide over the last 20 years. This study can aid researchers in decision-making by helping them understand the frontiers and hotspots in nutrition support and gastrointestinal cancer research. Future institutional and international collaboration is expected to accelerate the advancement of gastrointestinal cancer and nutritional support research and investigate more efficient treatment methods.

Current diagnosis tools for prostate cancer (PCa) such as serum PSA detection and prostate biopsy cannot distinguish dormant tumors from invasive malignancies, either be used as prognosis marker for castration resistant prostate cancer (CRPC), the lethal stage of PCa patients. Exosomes have been widely investigated as promising biomarkers for various diseases. We aim to characterize the proteomic and metabolomic profile of exosomes and to evaluate their potential value for the diagnosis of PCa, especially CRPC. We also investigate the functions of some specific exosome biomarkers in the progression of CRPC.

Integrated proteomics and metabolomics analysis were performed for plasma-derived exosomes collected from tumor-free controls (TFC), PCa and CRPC patients. Expression of specific exosomal proteins were further validated by targeted 4D-parallel reaction monitoring (PRM) mass spectrometry among the three cohorts. Tissue distribution and functional role of exosomal protein LRG1 was studied in clinical PCa tissue samples and cell line models.

Three potential exosomal protein markers were identified. The apolipoprotein E level in PCa samples was 1.7-fold higher than that in TFC (receiver operating characteristic value, 0.74). Similarly, the levels of exosome-derived leucine-rich alpha2-glycoprotein 1 (LRG1) and inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) in the CRPC group were 1.7 and 2.04 times, respectively, higher than those in the PCa group (ROC values, 0.84 and 0.85, respectively), indicating that LRG1 and ITIH3 could serve as predictive markers for CRPC. For metabolomic evaluation of exosomes, a series of differentially expressed metabolites were identified, and a combined metabolite panel showed ROC value of 0.94 for distinguishing PCa from TFC and 0.97 for distinguishing CRPC from PCa. Immunohistochemistry of tissue microarray showed that LRG1 protein was significantly upregulated in advanced prostate cancer and functional assay revealed that ectopic expression of LRG1 can significantly enhance the malignant phenotype of prostate cancer cells. More importantly, PCa cell derived LRG1-overexpressed exosomes remarkably promoted angiogenesis.

Integration of proteomics and metabolomics data generated proteomic and metabolic signatures of plasma exosomes that may facilitate discrimination of CRPC from PCa and TFC patients, suggesting the potential of exosomal proteins and metabolites as CRPC markers. The study also confirmed the important role of exosomal protein LRG1 in PCa malignant progression.

As a unique feature of malignant tumors, abnormal metabolism can regulate the immune microenvironment of tumors. However, the role of metabolic lncRNAs in predicting the prognosis and immunotherapy of gastric cancer (GC) has not been explored.

We downloaded the metabolism-related genes from the GSEA website and identified the metabolic lncRNAs. Co-expression analysis and Lasso Cox regression analysis were utilized to construct the risk model. To value the reliability and sensitivity of the model, Kaplan-Meier analysis and receiver operating characteristic curves were applied. The immune checkpoints, immune cell infiltration and tumor mutation burden of low- and high-risk groups were compared. Tumor Immune Dysfunction and Exclusion (TIDE) score was conducted to evaluate the response of GC patients to immunotherapy.

Twenty-three metabolic lncRNAs related to the prognosis of GC were obtained. Three cluster patterns based on metabolic lncRNAs could distinguish GC patients with different overall survival time (OS) effectively (p<0.05). The risk score model established by seven metabolic lncRNAs was verified as an independent prognostic indicator for predicting the OS of GC. The AUC value of the risk model was higher than TNM staging. The high-risk patients were accompanied by significantly increased expression of immune checkpoint molecules (including PD-1, PD-L1 and CTLA4) and increased tumor tolerant immune cells, but significantly decreased tumor mutation burden (TMB). Consistently, TIDE values of low-risk patients were significantly lower than that of high-risk patients.

The metabolic lncRNAs risk model can reliably and independently predict the prognosis of GC. The feature that simultaneously map the immune status of tumor microenvironment and TMB gives risk model great potential to serve as an indicator of immunotherapy.

Gastrointestinal malignancies are common digestive system tumor worldwide. Nucleoside analogues have been widely used as anticancer drugs for the treatment of a variety of conditions, including gastrointestinal malignancies. However, low permeability, enzymatic deamination, inefficiently phosphorylation, the emergence of chemoresistance and some other issues have limited its efficacy. The prodrug strategies have been widely applied in drug design to improve pharmacokinetic properties and address safety and drug-resistance issues. This review will provide an overview of the recent developments of prodrug strategies in nucleoside analogues for the treatment of gastrointestinal malignancies.

The Nobel Prize Winner (1931) Dr. Otto H. Warburg had established that the primary energy source of the cancer cell is aerobic glycolysis (the Warburg effect). He also postulated the hypothesis about "the prime cause of cancer", which is a matter of debate nowadays. Contrary to the hypothesis, his discovery was recognized entirely. However, the discovery had almost vanished in the heat of battle about the hypothesis. The prime cause of cancer is essential for the prevention and diagnosis, yet the effects that influence tumor growth are more important for cancer treatment. Due to the Warburg effect, a large amount of data has been accumulated on biochemical changes in the cell and the organism as a whole. Due to the Warburg effect, the recovery of normal biochemistry and oxygen respiration and the restoration of the work of mitochondria of cancer cells can inhibit tumor growth and lead to remission. Here, we review the current knowledge on the inhibition of abnormal glycolysis, neutralization of its consequences, and normalization of biochemical parameters, as well as recovery of oxygen respiration of a cancer cell and mitochondrial function from the point of view of classical biochemistry and organic chemistry.

Malignant bone tumors can inflict significant damage to affected bones, leaving patients to contend with issues like residual tumor cells, bone defects, and bacterial infections post-surgery. However, hydroxyapatite nanoparticles (nHAp), the principal inorganic constituent of natural bone, possess numerous advantages such as high biocompatibility, bone conduction ability, and a large surface area. Moreover, nHAp's nanoscale particle size enables it to impede the growth of various tumor cells via diverse pathways. This article presents a comprehensive review of relevant literature spanning the past 2 decades concerning nHAp and bone tumors. The primary goal is to explore the mechanisms responsible for nHAp's ability to hinder tumor initiation and progression, as well as to investigate the potential of integrating other drugs and components for bone tumor diagnosis and treatment. Lastly, the article discusses future prospects for the development of hydroxyapatite materials as a promising modality for tumor therapy.