The intricate interplay between organs can give rise to a multitude of physiological conditions. Disruptions such as inflammation or tissue damage can precipitate the development of chronic diseases such as tumors or diabetes mellitus (DM). While both lung cancer and DM are the consequences of disruptions in homeostasis, the relationship between them is intricate. This study sought to investigate the potential influence of DM on lung cancer by employing total-body dynamic PET imaging.

The present study proposes a framework for metabolic network analysis using total-body dynamic PET imaging of 20 lung cancer patients with DM (DM group) and 20 lung cancer patients without DM (Non-DM group), with the residuals of a third-order polynomial fit serving as an indicator of Pearson correlation.

The framework successfully captured the deviation of the DM group from the Non-DM group at both the edge and organ levels. At the edge level, there was a significant difference in the lesion- left ventricle (LV) between the DM and Non-DM groups (P < 0.05). Furthermore, we discovered a positive correlation between the absolute value of Z-score (ZCC) of lesion - LV and the duration of DM (R = 0.680, P < 0.001). At the organ level, there was a significant difference in the kidney, brain, and abdominal fat between the DM and Non-DM groups (P < 0.05).

This study demonstrated the feasibility of constructing metabolic networks to uncover complex alterations in lung cancer patients with DM. The findings contribute to understanding the systemic effects of DM on lung cancer metabolism and highlight the importance of personalized metabolic network analysis to comprehend the implications of concurrent diseases.

The pathogenesis of autoimmunity is incompletely understood which limits the development of effective therapies. New compelling evidence indicates that the pentose phosphate pathway (PPP) profoundly regulate lineage development in the immune system that are influenced by genetic and environmental factors during metabolic stress underlying the development of autoimmunity. The PPP provides two unique metabolites, ribose 5-phosphate for nucleotide biosynthesis in support of cell proliferation and NADPH for protection against oxidative stress. The PPP operates two separate branches, oxidative (OxPPP) and non-oxidative (NOxPPP). While the OxPPP functions in all organisms, the NOxPPP reflects adaptation to niche-specific metabolic requirements. The OxPPP primarily depends on glucose 6-phosphate dehydrogenase (G6PD), whereas transaldolase (TAL) controls the rate and directionality of metabolic flux though the NOxPPP. G6PD is essential for normal development but its partial deficiency protects from malaria. Although men and mice lacking TAL develop normally, they exhibit liver cirrhosis progressing to hepatocellular carcinoma. Mechanistic target of rapamycin-dependent loss of paraoxonase 1 drives autoimmunity and cirrhosis in TAL deficiency, while hepatocarcinogenesis hinges on polyol pathway activation via aldose reductase (AR). Accumulated polyols, such as erythritol, xylitol, and sorbitol, which are commonly used as non-caloric sweeteners, may act as pro-inflammatory oncometabolites under metabolic stress, such as TAL deficiency. The TAL/AR axis is identified as a checkpoint of pathogenesis and target for treatment of metabolic stress-driven systemic autoimmunity with relevance for inflammatory liver, renal and cardiovascular disorders, diabetes, carcinogenesis, and aging.

This paper examined the role of solute carrier family 2 member 1 (SLC2A1) in colorectal cancer (CRC) progression, focusing on its expression levels, functional implications, and regulatory mechanisms involving Yes-associated protein 1 (YAP1) and the Wnt signaling pathway.

GEO datasets (GSE14297, GSE18462, GSE40367) were analyzed to identify genes linked to metastasis in CRC, and TCGA-COAD system was used to analyze the expression pattern and prognostic values of SLC2A1 in CRC. Functional studies were conducted using CRC cell lines (Caco-2 and SW480). Cell viability, migration and invasion, and apoptosis were examined using EdU assays, Transwell assays, and flow cytometry. YAP1's regulatory role on SLC2A1 was investigated using ChIP-qPCR and luciferase reporter assays. The Wnt/β-catenin agonist SKL2001 was used for functional rescue experiments.

SLC2A1 was upregulated in CRC cells, and its upregulation was associated with tumor metastasis and unfavorable outcomes according to bioinformatics. Knockdown of SLC2A1 resulted in reduced cell viability, decreased migration, and increased apoptosis in Caco-2 and SW480 cells. Additionally, YAP1 was identified as a transcriptional activator of SLC2A1. Knockdown of YAP1 decreased SLC2A1 expression and reduced expression of Wnt target genes, thus suppressing malignant behavior of tumor cells. However, further overexpression of SLC2A1 restored cell viability and migration in YAP1-deficient cells. The YAP1- SLC2A1 axis activated the Wnt/β-catenin by reducing GSK3β activity.

SLC2A1 is critical in CRC progression, with YAP1 serving as a key regulator of its expression and function. The YAP1-SLC2A1-Wnt axis represents a potential therapeutic target for CRC, providing insights into metabolic adaptations that support tumor growth and metastasis.

Insufficient adenosine triphosphate (ATP) can reduce the synthesis of heat-stress-induced heat shock proteins (HSPs) to promote the efficiency of mild photothermal therapy (mPTT), thus the rational design of ATP-exhausted strategy based on nanotechnology is an effective approach to resuscitate mPTT. Herein, Nd3+ doped nanocrystals (NaYF4:Nd@CaF2, Nd-NCs) modified hollow mesoporous manganese oxide (H-MnOx) nanocomposite (H-MnOx@Nd-NCs, MN) is synthesized, and loaded with glucose transporters (GLUTs) inhibitor KL-11743, noted as MN-KL nanozyme. In tumor microenvironment (TME), MN-KL can react with overexpressed glutathione (GSH) to release KL-11743, which can suppress the synthesis of intracellular ATP at the source by blocking glucose uptake to inhibit HSPs expression, meanwhile, MN-KL catalyzes the production of ·O2 -/1O2/·OH and lipid peroxidation (LPO) to cleave existing HSPs. Through a two-pronged strategy with ATP inhibition and oxide accumulation, reducing the level of HSPs can be guaranteed for achieving efficient mPTT in both subcutaneous and in situ tumor models in mice. During this process, Nd-NCs can absorb near-infrared light and convert it into heat, and the quenched fluorescence of Nd-NCs by H-MnOx can be recovered through GSH-triggered biodegradation in tumors, thus the modification of Nd-NCs not only provides photothermal effect but also enables MN to own TME-activated fluorescence imaging.

Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs' roles in HCC and to determine the most effective ways to translate these findings into clinical practice.

Logic-gated strategies represent a promising approach to achieving highly selective cancer therapies. In this work, we present LG-AB (Logic-Gated Aza-BODIPY), an OFF-ON photothermal therapy (PTT) agent designed to selectively target cancer cells. LG-AB undergoes a red-shift in its maximum absorbance wavelength when activated in the tumor microenvironment, enabling the molecule to precisely generate heat in the cancerous tissue upon light irradiation. Unlike conventional activatable agents that rely on a single biomarker, LG-AB employs an AND logic-gated design, where glucose transporter 1 (GLUT1) overexpression facilitates targeted cellular uptake in cancer cells, followed by activation through elevated glutathione (GSH) levels. Beyond demonstrating photothermal efficacy in human lung cancer and murine breast cancer cells, we show that LG-AB effectively attenuates cancer progression through heat-induced apoptosis, with minimal off-target effects to surrounding tissues. The versatility of this strategy is further demonstrated through the development and application of LG-CPT (Logic-Gated Camptothecin), which utilizes the same logic-gated design. Our results show that enhancing specificity and limiting collateral damage can be broadly applied across different therapeutic agents.

Background: Tumor cells engage in continuous self-replication by utilizing a large number of resources and capabilities, typically within an aberrant metabolic regulatory network to meet their own demands. This metabolic dysregulation leads to the formation of the tumor microenvironment (TME) in most solid tumors. Nanomedicines, due to their unique physicochemical properties, can achieve passive targeting in certain solid tumors through the enhanced permeability and retention (EPR) effect, or active targeting through deliberate design optimization, resulting in accumulation within the TME. The use of nanomedicines to target critical metabolic pathways in tumors holds significant promise. However, the design of nanomedicines requires the careful selection of relevant drugs and materials, taking into account multiple factors. The traditional trial-and-error process is relatively inefficient. Artificial intelligence (AI) can integrate big data to evaluate the accumulation and delivery efficiency of nanomedicines, thereby assisting in the design of nanodrugs. Methods: We have conducted a detailed review of key papers from databases, such as ScienceDirect, Scopus, Wiley, Web of Science, and PubMed, focusing on tumor metabolic reprogramming, the mechanisms of action of nanomedicines, the development of nanomedicines targeting tumor metabolism, and the application of AI in empowering nanomedicines. We have integrated the relevant content to present the current status of research on nanomedicines targeting tumor metabolism and potential future directions in this field. Results: Nanomedicines possess excellent TME targeting properties, which can be utilized to disrupt key metabolic pathways in tumor cells, including glycolysis, lipid metabolism, amino acid metabolism, and nucleotide metabolism. This disruption leads to the selective killing of tumor cells and disturbance of the TME. Extensive research has demonstrated that AI-driven methodologies have revolutionized nanomedicine development, while concurrently enabling the precise identification of critical molecular regulators involved in oncogenic metabolic reprogramming pathways, thereby catalyzing transformative innovations in targeted cancer therapeutics. Conclusions: The development of nanomedicines targeting tumor metabolic pathways holds great promise. Additionally, AI will accelerate the discovery of metabolism-related targets, empower the design and optimization of nanomedicines, and help minimize their toxicity, thereby providing a new paradigm for future nanomedicine development.

Disulfidptosis, a novel form of disulfide stress-induced cell death involved in tumor progression, hasn't be well defined the function in tumor progression. And the clinical impacts of disulfidptosis-related genes (DRGs) in pancreatic adenocarcinoma (PAAD) remain largely unclear. In this study, we identified two distinct disulfidptosis subtypes and found that multilayer DRG alterations were associated with prognosis and TME infiltration characteristics. A three-gene prognostic signature was constructed to predict prognosis, and its clinical significance was characterized in the TCGA-PAAD cohort. The disulfidptosis signature was significantly correlated with prognosis, molecular subtype, CD8 T-cell infiltration, response to immune checkpoint inhibitors and chemotherapeutic drug sensitivity, and its predictive capability in PAAD patients was validated in multiple cohorts. Meanwhile, two anti-PD-L1 immunotherapy cohorts confirmed that low-risk patients exhibited substantially enhanced clinical response and treatment advantages. Furthermore, the expression patterns of DRGs were validated by quantitative real-time PCR. The expression and prognostic predictive capability of GLUT1 were verified by 87 PAAD patients from our cohort. These findings may help us understand the roles of DRGs in PAAD and the molecular characterization of disulfidptosis subtypes. The disulfidptosis signature could be a promising biomarker for prognosis, molecular subtypes, TME infiltration characteristics and immunotherapy efficacy.

Endothelial cell (EC) dysfunction within the aorta has long been recognized as a prominent contributor to the progression of atherosclerosis and the subsequent failure of vascular graft transplantation. However, the direct relationship between EC dysfunction and vascular remodeling remains to be investigated. In this study, we sought to address this knowledge gap by employing a strategy involving the release of glutamine synthetase (GS), which effectively activated endothelial metabolism and mitigates EC dysfunction. To achieve this, we developed GS-loaded small-diameter vascular grafts (GSVG) through the electrospinning technique, utilizing dual-component solutions consisting of photo-crosslinkable hyaluronic acid and polycaprolactone. Through an in vitro model of oxidized low-density lipoprotein-induced injury in human umbilical vein endothelial cells (HUVECs), we provided compelling evidence that the GSVG promoted the restoration of motility, angiogenic sprouting, and proliferation in dysfunctional HUVECs by enhancing cellular metabolism. Furthermore, the sequencing results indicated that these effects were mediated by miR-122-5p-related signaling pathways. Remarkably, the GSVG also exhibited regulatory capabilities in shifting vascular smooth muscle cells towards a contractile phenotype, mitigating inflammatory responses and thereby preventing vascular calcification. Finally, our data demonstrated that GS incorporation significantly enhanced re-endothelialization of vascular grafts in a ferric chloride-injured rat model. Collectively, our results offer insights into the promotion of re-endothelialization in vascular grafts by restoring dysfunctional ECs through the augmentation of cellular metabolism.

Organoids mimic human organ function, offering insights into development and disease. However, non-destructive, real-time monitoring is lacking, as traditional methods are often costly, destructive, and low-throughput. In this article, a non-destructive chemical tomographic strategy is presented for decoding cyto-proteo-genomics of organoid using volatile signaling molecules, hereby, Volatile Organic Compounds (VOCs), to indicate metabolic activity and development of organoids. Combining a hierarchical design of graphene-based sensor arrays with AI-driven analysis, this method maps VOC spatiotemporal distribution and generate detailed digital profiles of organoid morphology and proteo-genomic features. Lens- and label-free, it avoids phototoxicity, distortion, and environmental disruption. Results from testing organoids with the reported chemical tomography approach demonstrate effective differentiation between cyto-proteo-genomic profiles of normal and diseased states, particularly during dynamic transitions such as epithelial-mesenchymal transition (EMT). Additionally, the reported approach identifies key VOC-related biochemical pathways, metabolic markers, and pathways associated with cancerous transformations such as aromatic acid degradation and lipid metabolism. This real-time, non-destructive approach captures subtle genetic and structural variations with high sensitivity and specificity, providing a robust platform for multi-omics integration and advancing cancer biomarker discovery.

Hepatocellular carcinoma features extensive metabolic reprogramming. This includes alterations in major biochemical pathways such as glycolysis, the pentose phosphate pathway, amino acid metabolism and fatty acid metabolism. Moreover, there is a complex interplay among these altered pathways, particularly involving acetyl-CoA (coenzyme-A) metabolism and redox homeostasis, which in turn influences reprogramming of other metabolic pathways. Understanding these metabolic changes and their interactions with cellular signaling pathways offers potential strategies for the targeted treatment of hepatocellular carcinoma and improved patient outcomes. This review explores the specific metabolic alterations observed in hepatocellular carcinoma and highlights their roles in the progression of the disease.

Breast cancer is a widely prevalent and devastating morbidity that affects millions of women around the world. Conventional treatment options for breast cancer include surgery, chemotherapy, and radiotherapy. However, these therapies can frequently have adverse side effects and may not be effective for all patients. In recent years, there has been an increasing interest in the development of targeted therapies for breast cancer. Glut-1, a key glucose transporter that is often overexpressed in breast cancer cells, is a potential candidate for targeted therapies. Glut-1 is crucial for basal glucose transport into cancer cells and is necessary for their rapid growth and survival. Several Glut-1 inhibitors - both natural and synthetic small molecules - have been identified and used as anticancer agents. In this chapter, we summarize the different approaches of Glut-1 inhibition in breast cancer and the mode of inhibition used by various Glut-1 inhibitors. Further understanding of the mechanisms underlying the efficacy of Glut-1 inhibitors in breast cancer treatment may provide crucial insights that can lead to the advancement of current treatment strategies. The functional inhibition of Glut-1 by specific Glut-1 inhibitors is being explored as a potential treatment modality for breast cancer. This approach holds great promise for improving the therapeutic efficacy of breast cancer treatment and minimizing the side effects associated with conventional therapies.

Soluble vector family member 6 (SLC2A6) has been implicated in the aggressiveness and poor prognosis of various cancers, yet its specific role in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study utilized multiple databases to investigate the relationship between SLC2A6 expression and clinical stage, methylation status, drug sensitivity, immune infiltration, and immune checkpoint regulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Furthermore, in vitro and in vivo experiments were performed to assess the impact of SLC2A6 knockout on the proliferation, migration, invasion, and underlying mechanisms in hepatocellular carcinoma (LIHC) cells. SLC2A6 expression was significantly correlated with tumor prognosis, clinical stage, and methylation levels, and was found to influence immune cell infiltration and immune checkpoint gene expression. In LIHC, SLC2A6 was associated with key biological processes, including the cell cycle, P53 signaling, and ferroptosis. Knockdown of SLC2A6 markedly suppressed the proliferation, migration, and invasion of HCC cells, with this inhibition being closely tied to the ferroptosis pathway. SLC2A6 plays a pivotal role in the regulation of pan-cancer processes, particularly in tumor prognosis and immune-related mechanisms. In LIHC, it emerges as a potential prognostic biomarker and therapeutic target for the regulation of ferroptosis, offering new insights for targeted cancer therapies.

The interpretation of the biochemistry of immune metabolism could be considered an attractive scientific field of biomedicine research. In this review, the role of glycolysis in macrophage polarization is discussed together with mitochondrial metabolism in cancer cells. In the first part, the focus is on the Warburg effect and redox metabolism during macrophage polarization, cancer development, and management of the immune response by the cancer cells. The second part addresses the possibility of impacts on the Warburg effect through targeting peroxisome proliferator-activated receptors (PPARs). This could be an activator of native immune responses. Because of the reported serious adverse effects of using synthetic ligands for PPARs in combination with chemotherapeutics, searches for less toxic and more active PPAR inhibitors, as well as blocking undesirable cellular PPAR-dependent processes, are in progress. On the other hand, recent research in modern immunotherapy has focused on the search for gentle immune-modulating natural compounds with harmless synergistic chemotherapeutic efficacy that can be used as an adjuvant. It is a well-known fact that the plant kingdom is a source of important therapeutic agents with multifaceted effectiveness. One of these is the known association with PPAR activities. In this regard, the secondary metabolites extracted from plants could change the game.

Prostate cancer is the second most common cancer in men, accounting for 14.1% of new cancer cases in 2020. The aggressiveness of prostate cancer is highly variable, depending on its grade and stage at the time of diagnosis. Despite recent advances in prostate cancer treatment, some patients still experience recurrence or even progression after undergoing radical treatment. Accurate initial staging and monitoring for recurrence determine patient management, which in turn affect patient prognosis and survival. Classical imaging has limitations in the diagnosis and treatment of prostate cancer, but the use of novel molecular probes has improved the detection rate, specificity, and accuracy of prostate cancer detection. Molecular probe-based imaging modalities allow the visualization and quantitative measurement of biological processes at the molecular and cellular levels in living systems. An increased understanding of tumor biology of prostate cancer and the discovery of new tumor biomarkers have allowed the exploration of additional molecular probe targets. The development of novel ligands and advances in nano-based delivery technologies have accelerated the research and development of molecular probes. Here, we summarize the use of molecular probes in positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound imaging, and provide a brief overview of important target molecules in prostate cancer.

Carbohydrates, lipids, bile acids, various inorganic salt ions and organic acids are the main nutrients or indispensable components of the human body. Dysregulation in the processes of absorption, transport, metabolism, and excretion of these metabolites can lead to the onset of severe metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, gout and hyperbilirubinemia. As the second largest membrane receptor supergroup, several major families in the solute carrier (SLC) supergroup have been found to play key roles in the transport of substances such as carbohydrates, lipids, urate, bile acids, monocarboxylates and zinc ions. Based on common metabolic dysregulation and related metabolic substances, we explored the relationship between several major families of SLC supergroup and metabolic diseases, providing examples of drugs targeting SLC proteins that have been approved or are currently in clinical/preclinical research as well as SLC-related diagnostic techniques that are in clinical use or under investigation. By highlighting these connections, we aim to provide insights that may contribute to the development of improved treatment strategies and targeted therapies for metabolic disorders.

Glioblastoma continues to pose a major global health challenge due to its incurable nature. The need for new strategies to combat this devastating tumor is therefore paramount. Nanotechnology offers unique opportunities to develop innovative and more effective therapeutic approaches. However, most nanosystems developed to treat glioblastomas, especially those based on metallic nanoparticles (NPs), have proven unsuccessful due to their inability to efficiently target these tumors, which are particularly inaccessible due to the restrictions imposed by the blood-brain tumor barrier (BBTB). Here, an innovative strategy is presented to efficiently target metallic NPs to glioblastomas through glucose transporters (GLUT) overexpressed on the endothelial cells of glioblastoma microvasculature, particularly GLUT1. Specifically, Iron Oxide Nanoparticles (IONPs) are functionalized with glucuronic acid to promote GLUT-mediated transcytosis which is drastically boosted by inducing mild hypoglycemia. This metabolically-driven active targeting strategy has yielded unprecedented efficacy in targeting metallic NPs to glioblastomas. Moreover, these IONPs, designed to act as magnetic hyperthermia (MH) mediators, are used to conduct a proof-of-concept preclinical study on MRI-tracked MH therapy following intravenous administration, resulting in significant tumor growth delay. These findings demonstrate unparalleled efficiency in glioblastoma targeting and lay the ground for developing alternative therapeutic strategies to combat glioblastoma.

Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.

Prostate cancer is one of the major causes of morbidity and mortality in men worldwide. Most patients with prostate cancer will turn into end-of-life stage when those tumor cells become metastatic castration-resistant prostate cancer (mCRPC). The mCRPC subsequently developed a resistance to androgen signaling. The current regimens for mCRPC therapy are still ineffective. Much evidence from in vitro and in vivo studies explored the roles of therapeutic interventions targeted at the mitochondria and programmed cell death for prostate cancer therapy. The present review will focus on the recent medications which targeted at mitochondria and programmed cell death in mCRPC and the significant findings from each study will be summarized and discussed. Development of therapeutic interventions, particularly at mitochondrial and cytotoxic targets for treatment of mCRPC without inducing cellular toxicity of normal tissues will be considered as the novel therapeutic strategy for mCRPC.

Double hydrophilic diblock copolymers (G20A100 and G100A98), composed of non-charged poly(glycosyloxyethyl methacrylate) (PGEMA, G) and cationic poly((3-acrylamidopropyl)trimethylammonium chloride), were synthesized via reversible addition-fragementation chain transfer (RAFT) radical polymerization. Likewise, diblock copolymers (G20S80 and G100S78), composed of PGEMA and anionic poly(2-acrylamido-2-methylpropanesulfonate) were synthesized via RAFT. The subscripts in these abbreviations indicate the degree of polymerization (DP) of each block. Polyion complex (PIC) aggregates (G20A100/G20S80 and G100A98/G100S78) were formed through electrostatic interactions by combining oppositely charged diblock copolymers with matched DPs for charge neutralization. The hydrodynamic radii of the G20A100/G20S80 and G100A98/G100S78 PIC aggregates were 77.4 and 26.2 nm, respectively, with zeta potentials close to 0 mV. The G20A100/G20S80 PIC micelles tend to form intermicellar aggregates, resulting in an increase in the particle size over time. In contrast, G100A98/G100S78 PIC micelles exhibited colloidal stability with a constant spherical core-shell shape, which was unaffected by time. The morphology and stability of the PIC aggregates depend upon the DP ratio of PGEMA and oppositely charged polyelectrolyte blocks. Both G20A100/G20S80 and G100A98/G100S78 PIC aggregates dissociated above 0.8 M NaCl due to the screening effect of NaCl.

The postmenopausal decrease in circulating estradiol (E2) levels has been shown to contribute to several adverse physiological and psychiatric effects. To elucidate the molecular effects of E2 on the brain, we examined differential gene expression and DNA methylation (DNAm) patterns in the nonhuman primate brain following ovariectomy (Ov) and subsequent subcutaneous bioidentical E2 chronic treatment. We identified several dysregulated molecular networks, including MAPK signaling and dopaminergic synapse response, that are associated with ovariectomy and shared across two different brain areas, the occipital cortex (OC) and prefrontal cortex (PFC). The finding that hypomethylation (p = 1.6 × 10-51) and upregulation (p = 3.8 × 10-3) of UBE2M across both brain regions provide strong evidence for molecular differences in the brain induced by E2 depletion. Additionally, differential expression (p = 1.9 × 10-4; interaction p = 3.5 × 10-2) of LTBR in the PFC provides further support for the role E2 plays in the brain, by demonstrating that the regulation of some genes that are altered by ovariectomy may also be modulated by Ov followed by hormone replacement therapy (HRT). These results present real opportunities to understand the specific biological mechanisms that are altered with depleted E2. Given E2's potential role in cognitive decline and neuroinflammation, our findings could lead to the discovery of novel therapeutics to slow cognitive decline. Together, this work represents a major step toward understanding molecular changes in the brain that are caused by ovariectomy and how E2 treatment may revert or protect against the negative neuro-related consequences caused by a depletion in estrogen as women approach menopause.

Although accounting for only a small amount of skin cancers, melanoma contributes prominently to skin cancer-related deaths, which are mostly caused by metastatic diseases, and lymphatic metastasis constitutes the main route. In this review, we concentrate on the metabolic mechanisms of tumor lymph node (LN) metastasis in melanoma. Two hypotheses of melanoma LN metastasis are introduced, which are the premetastatic niche (PMN) and parallel progression model. Dysregulation of oxidative stress, lactic acid concentration, fatty acid synthesis, amino acid metabolism, autophagy, and ferroptosis construct the metabolic mechanisms in LN metastasis of melanoma. Moreover, melanoma cells also promote LN metastasis by interacting with non-tumor cells through metabolic reprogramming in TIME. This review will deepen our understanding of the mechanism of lymph node metastasis in melanoma.

S-Palmitoylation has been widely noticed and studied in a variety of diseases. Increasing evidence suggests that S-palmitoylation modification also plays a key role in Glioblastoma (GBM). The zDHHC family, as an important member of S-palmitoyltransferases, has received extensive attention for its function and mechanism in GBM which is one of the most common primary malignant tumors of the brain and has an adverse prognosis. This review focuses on the zDHHC family, essential S-palmitoyltransferases, and their involvement in GBM. By summarizing recent studies on zDHHC molecules in GBM, we highlight their significance in regulating critical processes such as cell proliferation, invasion, and apoptosis. Specifically, members of zDHHC3, zDHHC4, zDHHC5 and others affect key processes such as signal transduction and phenotypic transformation in GBM cells through different pathways, which in turn influence tumorigenesis and progression. This review systematically outlines the mechanism of zDHHC family-mediated S-palmitoylation modification in GBM, emphasizes its importance in the development of this disease, and provides potential targets and strategies for the treatment of GBM. It also offers theoretical foundations and insights for future research and clinical applications.

Despite the advent of various medical interventions for cancer treatment, the disease continues to pose a formidable global health challenge, necessitating the development of new therapeutic approaches for more effective treatment outcomes. Photodynamic therapy (PDT), which utilizes light to activate a photosensitizer to produce cytotoxic reactive oxygen species (ROS) for eradicating cancer cells, has emerged as a promising approach for cancer treatment due to its high spatiotemporal precision and minimal invasiveness. However, the widespread clinical use of PDT faces several challenges, including the inefficient production of ROS in the hypoxic tumor microenvironment, the limited penetration depth of light in biological tissues, and the inadequate accumulation of photosensitizers at the tumor site. Over the past decade, there has been increasing interest in the utilization of photofunctional transition metal complexes as photosensitizers for PDT applications due to their intriguing photophysical and photochemical properties. This review provides an overview of the current design strategies used in the development of transition metal complexes as innovative phototherapeutics, aiming to address the limitations associated with PDT and achieve more effective treatment outcomes. The current challenges and future perspectives on the clinical translation of transition metal complexes are also discussed.

Pyrene-urea derivatives and acetate anions were used to investigate the excited-state intermolecular proton transfer (ESPT) reaction, where a molecule undergoes intermolecular proton transfer to form a tautomer species in the excited state. Since ESPT occurs when intermolecular hydrogen bonds exist between urea compounds and acetate species, we hypothesize that this reaction might be influenced by compounds with hydroxy groups. In this study, cyclodextrins, saccharides, and ethanol were examined to assess the effects of hydroxy groups on the ESPT reaction. After introducing various hydroxy compounds into the urea-acetate system in dimethylformamide, we observed differences in the fluorescence spectra and fluorescence decay curves. These differences indicate varying interactions between the hydroxy compounds and complexes, leading to distinct fluorescence lifetime behaviors, which makes fluorescence lifetime imaging technology particularly suitable.

Lactylation, a post-translational modification, is increasingly recognized for its role in cancer progression. This study investigates its prevalence and impact in oral squamous cell carcinoma (OSCC).

Immunohistochemical staining of 81 OSCC cases shows lactylation levels correlate with malignancy grading. Proteomic analyses of six OSCC tissue pairs reveal 2765 lactylation sites on 1033 proteins, highlighting its extensive presence. These modifications influence metabolic processes, molecular synthesis, and transport. CAL27 cells are subjected to cleavage under targets and tagmentation assay for accessible-chromatin with high-throughput sequencing, and transcriptomic sequencing pre- and post-lactate treatment, with 217 genes upregulated due to lactylation. Chromatin immunoprecipitation-quantitative PCR and real-time fluorescence quantitative PCR confirm the regulatory role of lactylation at the K146 site of dexh-box helicase 9 (DHX9), a key factor in OSCC progression. CCK8, colony formation, scratch healing, and Transwell assays demonstrate that lactylation mitigates the inhibitory effect of DHX9 on OSCC, thereby promoting its occurrence and development.

Lactylation actively modulates gene expression in OSCC, with significant effects on chromatin structure and cellular processes. This study provides a foundation for developing targeted therapies against OSCC, leveraging the role of lactylation in disease pathogenesis.

In this work, the HR MAS NMR (high-resolution magic-angle spinning nuclear magnetic resonance) spectroscopy technique was combined with standard histological examinations to investigate the metabolic features of high-grade serous ovarian cancer (HGSOC) with a special focus on the relation between a metabolic profile and a cancer cell fraction. The studied group consisted of 44 patients with HGSOC and 18 patients with benign ovarian tumors. Normal ovarian tissue was also excised from 13 control patients. The metabolic profiles of 138 tissue specimens were acquired on a Bruker Avance III 400 MHz spectrometer. The NMR spectra of the HGSOC samples could be discriminated from those acquired from the non-transformed tissue and were shown to depend on tumor purity. The most important features that differentiate the samples with a high fraction of cancer cells from the samples containing mainly fibrotic stroma are the increased intensities in the spectral regions corresponding to phosphocholine/glycerophosphocholine, phosphoethanolamine/serine, threonine, uridine nucleotides and/or uridine diphosphate (UDP) nucleotide sugars. Higher levels of glutamine, glutamate, acetate, lysine, alanine, leucine and isoleucine were detected in the desmoplastic stroma within the HGSOC lesions compared to the stroma of benign tumors. The HR MAS NMR analysis of the metabolic composition of the epithelial and stromal compartments within HGSOC contributes to a better understanding of the disease's biology.

Cancer is the result of complex interactions of intrinsic and extrinsic cell processes, which promote sustained proliferation, resistance to apoptosis, reprogramming and reorganization. The evolution of any type of cancer emerges from the role of the microenvironmental conditions and their impact of some molecular complexes on certain signalling pathways. The understanding of the early onset of cancer requires a multiscale analysis of the cellular microenvironment. In this paper, we analyse a qualitative multiscale model of pancreatic adenocarcinoma by modelling the cellular microenvironment through elastic cell interactions and their intercellular communication mechanisms, such as growth factors and cytokines. We focus on the low-grade dysplasia (PanIN 1) and moderate dysplasia (PanIN 2) stages of pancreatic adenocarcinoma. To this end, we propose a gene-regulatory network associated with the processes of proliferation and apoptosis of pancreatic cells and its kinetics in terms of delayed differential equations to mimic cell development. Likewise, we couple the cell cycle with the spatial distribution of cells and the transport of growth factors to show that the adenocarcinoma evolution is triggered by inflammatory processes. We show that the oncogene RAS may be an important target for developing anti-inflammatory strategies that limit the emergence of more aggressive adenocarcinomas.

Gastrointestinal (GI) cancers are the leading cause of new cancer cases and cancer-related deaths worldwide. The treatment strategies for patients with GI tumors have focused on oncogenic molecular profiles associated with tumor cells. Recent evidence has demonstrated that the tumor cell functions are modulated by its microenvironment, compromising fibroblasts, extracellular matrices, microbiome, immune cells, and the enteric nervous system. Along with the tumor microenvironment components, alterations in key metabolic pathways have emerged as a hallmark of tumor cells. From these perspectives, this review will highlight the functions of different cellular components of the GI tumor microenvironment and their implications for treatment. Furthermore, we discuss the major metabolic reprogramming in GI tumor cells and how understanding metabolic rewiring could lead to new therapeutic strategies. Finally, we briefly summarize the targeted agents currently being studied in GI cancers. Understanding the complex interplay between tumor cell-intrinsic and -extrinsic factors during tumor progression is critical for developing new therapeutic strategies.

Human glucose transporters (GLUTs) facilitate the uptake of hexoses into cells. In cancer, the increased proliferation necessitates higher expression of GLUTs, with particular emphasis on GLUT1 and GLUT3. Thus, inhibiting GLUTs holds promise as an anticancer therapy by starving these cells of fuel. Ganoderic acid A (GAA), a triterpene found in Ganoderma lucidum, has anticancer and antidiabetic properties. Recent studies show that GAA reduces glucose uptake in cancer cells, which indicates that GAA may affect GLUT1/GLUT3 by inhibiting glucose uptake. Therefore, this study aimed to inspect whether GAA could target GLUT1/GLUT3 and play an inhibitory role in changing their endofacial and exofacial conformations. To this end, AlphaFold2 was employed to model the endofacial and exofacial conformations of GLUT3 and GLUT1, respectively. Molecular docking, molecular dynamics simulation, cell viability, cellular thermal shift assays (CETSA), glucose uptake, qPCR, and western blotting were harnessed. In comparison to the endofacial (cytochalasin B) and exofacial (phloretin) GLUT1/3 inhibitors, the computational findings unveiled GAA's capacity to bind and stabilize GLUT1/3 in their two conformational states, with a preference for binding the endofacial conformation. A low, non-cytotoxic dose of GAA thermally stabilized both transporters and inhibited glucose uptake in human lung cancer cells, similar to cytochalasin B and phloretin. In conclusion, this study has unearthed novel functionalities of GAA, suggesting its potential utility in cancer therapy by targeting glucose metabolism.

Breast cancer (BC) is a heterogeneous malignancy with a dismal prognosis. Disulfidptosis is a novel type of regulated cell death that happens in the presence of glucose deficiency and is linked to the metabolic process of glycolysis. However, the mechanism of action of disulfidptosis and glycolysis-related genes (DGRG) in BC, as well as their prognostic value in BC patients, remain unknown. After identifying the differentially expressed DGRG in normal and BC tissues, a number of machine learning algorithms were utilized to select essential prognostic genes to develop a model, including SLC7A11, CACNA1H, SDC1, CHST1, and TFF3. The expression characteristics of these genes were then examined using single-cell RNA sequencing, and BC was classified into three clusters using "ConsensusClusterPlus" based on these genes. The DGRG model's median risk score can categorize BC patients into high-risk and low-risk groups. Furthermore, we investigated variations in clinical landscape, immunoinvasion analysis, tumor immune dysfunction and rejection (TIDE), and medication sensitivity in patients in the DGRG model's high- and low-risk groups. Patients in the low-risk group performed better on immunological and chemotherapeutic therapies and had lower TIDE scores. In conclusion, the DGRG model we developed has significant clinical application potential because it can accurately predict the prognosis of BC, TME, and pharmacological treatment responses.

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.

Luminescence imaging is a powerful and versatile technique for investigating cell physiology and pathology in living systems, making significant contributions to life science research and clinical diagnosis. In recent years, luminescent transition metal complexes have gained significant attention for diagnostic and therapeutic applications due to their unique photophysical and photochemical properties. In this Review, we provide a comprehensive overview of the recent development of luminescent transition metal complexes for bioimaging and biosensing applications, with a focus on transition metal centers with a d6, d8, and d10 electronic configuration. We elucidate the structure-property relationships of luminescent transition metal complexes, exploring how their structural characteristics can be manipulated to control their biological behavior such as cellular uptake, localization, biocompatibility, pharmacokinetics, and biodistribution. Furthermore, we introduce the various design strategies that leverage the interesting photophysical properties of luminescent transition metal complexes for a wide variety of biological applications, including autofluorescence-free imaging, multimodal imaging, organelle imaging, biological sensing, microenvironment monitoring, bioorthogonal labeling, bacterial imaging, and cell viability assessment. Finally, we provide insights into the challenges and perspectives of luminescent transition metal complexes for bioimaging and biosensing applications, as well as their use in disease diagnosis and treatment evaluation.

Chemotherapy is one of the main treatments for oral squamous cell carcinoma (OSCC), especially as a combined modality approach with and after surgery or radiotherapy. Limited therapeutic efficiency and serious side effects greatly restrict the clinical performance of chemotherapeutic drugs. The development of smart nanomedicines has provided new research directions, to some extent. However, the involvement of complex carrier compositions inevitably brings biosafety concerns and greatly limits the "bench-to-bed" translation of most nanomedicines reported. In this study, a carrier-free self-assembled prodrug was fabricated by two triterpenes (glycyrrhetinic acid, GA and ginsenoside Rh2, Rh2) isolated from medicinal plants, licorice, and ginseng, for the targeted and highly effective treatment of OSCC. Reactive oxygen species (ROS) self-supplied molecule TK-GA2 was synthesized with ROS-responsive thioketal linker and prodrug was prepared by a rapid-solvent-exchange method with TK-GA2 and Rh2. After administration, oral tumor cells transported large amounts of prodrugs with glucose ligands competitively. Endogenous ROS in oral tumor cells then promoted the release of GA and Rh2. GA further evoked the generation of a large number of ROS to help self-boosted drug release and increase oxidative stress, synergistically causing tumor cell apoptosis with Rh2. Overall, this carrier-free triterpene-based prodrug might provide a preeminent opinion on the design of effective chemotherapeutics with low systemic toxicity against OSCC.

Hypoglycemia is a rare complication of diffuse large B-cell lymphoma. We are presenting a case of 67-year-old woman presented to her primary care physician with fatigue and hyperhidrosis. Laboratory evaluation revealed a glucose level of 1.9 mmol/L. Computed tomographic scan of the abdomen and subsequent positron emission tomographic scan revealed extensive lymphadenopathy. The patient was then diagnosed with CD5-positive-diffuse large B-cell lymphoma and developed recurrent hypoglycemia despite continuous infusion of glucose. Following immunochemotherapy, hypoglycemia was resolved. Several explanations have been postulated but the exact pathophysiology is not well understood. Further investigation is warranted to more clearly define the pathophysiology of persistent hypoglycemia in patients with diffuse large B-cell lymphoma.

Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

Reprogramming of energy metabolism is a well-established hallmark of cancer, with aerobic glycolysis classically considered a prominent feature. We investigate the heterogeneity in glucose metabolism pathways within resectable primary lung adenocarcinoma and its clinical significance.

Using The Cancer Genome Atlas data, RNA expressions were extracted from 489 primary lung adenocarcinoma samples. Prognostic influence of glycolytic, aerobic, and mitochondrial markers (monocarboxylate transporter [MCT]4, MCT1, and translocase of outer mitochondrial membrane 20, respectively) was assessed using Kaplan-Meier analysis. Clustering of 35 genes involved in glucose metabolism was performed using the k-means method. The clusters were then analyzed for associations with demographic, clinical, and pathologic variables. Overall survival was assessed using the Kaplan-Meier estimator. Multivariate analysis was performed to assess the independent prognostic value of cluster membership.

Classical statistical approach showed that higher expression of MCT4 was associated with a significantly worse prognosis. Increased expression of translocase of outer mitochondrial membrane 20 was associated with a nonsignificant trend toward better prognosis, and increased expression of MCT1 was associated with a better outcome. Clustering identified 3 major metabolic phenotypes, dominantly hypometabolic, dominantly oxidative, and dominantly mixed oxidative/glycolytic with significantly different pathologic stage distribution and prognosis; mixed oxidative/glycolytic was associated with worse survival. Cluster membership was independently associated with survival.

This study demonstrates the existence of distinct glucose metabolism clusters in resectable lung adenocarcinoma, providing valuable prognostic information. The findings highlight the potential relevance of considering metabolic profiles when designing strategies for reprogramming energy metabolism. Further studies are warranted to validate these findings in different cancer types and populations.

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

The research on the correlation or causality between gut microbiota and the occurrence, development, and treatment of colorectal cancer (CRC) is receiving increasing emphasis. At the same time, the incidence and mortality of colorectal cancer vary among individuals and regions, as does the gut microbiota. In order to gain a better understanding of the characteristics of the gut microbiota in CRC patients and the differences between different regions, we initially compared the gut microbiota of 25 CRC patients and 26 healthy controls in the central region of China (Hubei Province) using 16S rRNA high-throughput sequencing technology. The results showed that Corynebacterium, Enterococcus, Lactobacillus, and Escherichia-Shigella were significantly enriched in CRC patients. In addition, we also compared the potential differences in functional pathways between the CRC group and the healthy control group using PICRUSt's functional prediction analysis. We then analyzed and compared it with five cohort studies from various regions of China, including Central, East, and Northeast China. We found that geographical factors may affect the composition of intestinal microbiota in CRC patients. The composition of intestinal microbiota is crucial information that influences colorectal cancer screening, early detection, and the prediction of CRC treatment outcomes. This emphasizes the importance of conducting research on CRC-related gut microbiota in various regions of China.

Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.

The surrounding non-cancer cells and tumor cells that make up the tumor microenvironment (TME) have various metabolic rhythms. TME metabolic heterogeneity is influenced by the intricate network of metabolic control within and between cells. DNA, protein, transport, and microbial levels are important regulators of TME metabolic homeostasis. The effectiveness of immunotherapy is also closely correlated with alterations in TME metabolism. The response of a tumor patient to immunotherapy is influenced by a variety of variables, including intracellular metabolic reprogramming, metabolic interaction between cells, ecological changes within and between tumors, and general dietary preferences. Although immunotherapy and targeted therapy have made great strides, their use in the accurate identification and treatment of tumors still has several limitations. The function of TME metabolic heterogeneity in tumor immunotherapy is summarized in this article. It focuses on how metabolic heterogeneity develops and is regulated as a tumor progresses, the precise molecular mechanisms and potential clinical significance of imbalances in intracellular metabolic homeostasis and intercellular metabolic coupling and interaction, as well as the benefits and drawbacks of targeted metabolism used in conjunction with immunotherapy. This offers insightful knowledge and important implications for individualized tumor patient diagnosis and treatment plans in the future.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.