Tumor-associated macrophages (TAMs) play a multifaceted role in the tumor microenvironment, notably by suppressing antitumor immune responses through immunosuppressive mechanisms. TAMs secrete a range of cytokines that simultaneously inhibit T cell function and foster a microenvironment that supports tumor progression and dissemination. Our study has delved into the intricate relationship between the metabolic reprogramming of TAMs and their impact on tumor progression. Mitochondrial metabolic reprogramming mediated by the SENP1-Sirt3 axis altered the dynamics and activity of tumor-infiltrating immune cells, including macrophages and CD8+ T lymphocytes. SENP1-Sirt3 axis increases the level of acetyl-CoA in macrophage mitochondria, which in turn promotes cholesterol biosynthesis in macrophages. The upregulation of cholesterol synthesis is a key factor in driving macrophage polarization towards the immunosuppressive M2 phenotype, which in turn supports tumor development. Notably, increased cholesterol levels contributed to a reduction in the number and activity of CD8+ T cells, which are essential for mounting an effective immune response against cancer cells. These findings suggest that targeting cholesterol biosynthesis in TAMs may be a promising strategy for cancer immunotherapy. SIGNIFICANCE: Activation of the SENP1-Sirt3 axis initiates mitochondrial metabolic reprogramming in tumor-associated macrophages (TAMs), leading to enhanced cholesterol and acetyl-CoA production, M2 macrophage polarization, and impaired CD8+ T cell anti-tumor responses.

The mutated in colorectal cancer (MCC) gene is closely associated with the onset and progression of colorectal cancer. MCC plays a critical role in regulating the cell cycle and various signaling pathways and is recognized to inhibit cancer cell proliferation via the β-catenin signaling pathway. β-catenin is a key component of the WNT signaling pathway that influences cell growth, differentiation, survival, and migration, thereby positioning MCC as an important tumor suppressor. Notably, MCC has also been implicated in other cancer types, including lung, liver, and brain cancers. However, the precise mechanisms by which MCC functions in these malignancies remain inadequately understood. Comprehensive investigations into the interactions among MCC, various signaling pathways, and metabolic processes are essential for uncovering the molecular mechanisms of cancer and the pathological features characteristic of different cancer stages. This review presents the structural characteristics of MCC and its cell growth regulation mechanisms and functional roles within tissues, with the aims of enhancing our understanding of the role of MCC in cancer biology and highlighting potential therapeutic strategies targeting this gene.

Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.

The development of precise molecular biomarkers for breast cancer prognosis holds immense potential to improve treatment outcomes. This study aimed to investigate the role of amino acid metabolism genes as predictive markers for breast cancer prognosis and their association with the immune-tumour microenvironment. By employing advanced machine learning algorithms and bioinformatics analysis techniques, the impact of amino acid metabolism-related genes (AAMRGs) on the immune status and overall survival of patients with breast cancer was examined. An AAMRG-based risk model was established to assess the prognostic significance. Validated risk models (AIMP2, IYD, and QARS1) accurately predicted patient outcomes [1 y: 0.87 (0.96-0.78); 3 y: 0.82 (0.87-0.76); 5 y: 0.80 (0.86-0.75)]. Furthermore, this study revealed evidence suggesting that QARS1 may influence breast cancer cell proliferation through methionine metabolism. This analysis provides valuable insights into the mechanisms of breast cancer, emphasizing the significance of AAMRGs as prognostic biomarkers and potential therapeutic targets for optimizing personalized treatment strategies.

The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.

Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely, how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.

Metabolic disorders of cardiomyocytes play an important role in the progression of various cardiovascular diseases. Metabolic reprogramming can provide ATP to cardiomyocytes and protect them during diseases, but this transformation also leads to adverse consequences such as oxidative stress, mitochondrial dysfunction, and eventually aggravates myocardial injury. Moreover, abnormal accumulation of metabolites induced by metabolic reprogramming of cardiomyocytes alters the cardiac microenvironment and affects the metabolism of immune cells. Immunometabolism, as a research hotspot, is involved in regulating the phenotype and function of immune cells. After myocardial injury, both cardiac resident immune cells and heart-infiltrating immune cells significantly contribute to the inflammation, repair and remodeling of the heart. In addition, metabolites generated by the metabolic reprogramming of immune cells can further affect the microenvironment, thereby affecting the function of cardiomyocytes and other immune cells. Therefore, metabolic reprogramming and abnormal metabolite levels may serve as a bridge between cardiomyocytes and immune cells, leading to the development of cardiovascular diseases. Herein, we summarize the metabolic relationship between cardiomyocytes and immune cells in cardiovascular diseases, and the effect on cardiac injury, which could be therapeutic strategy for cardiovascular diseases, especially in drug research.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a unique tumor microenvironment (TME) that plays pivotal roles in cancer progression, angiogenesis, metastasis, and drug resistance. This complex and dynamic ecosystem comprises cancer cells, stromal cells, and extracellular matrix (ECM) components, which interact synergistically to drive cancer aggressiveness. Among the stromal cells, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs), mainly accepted as a group of CAFs, are central players in shaping the desmoplastic, hypoxic, and immunosuppressive stroma of PDAC. PSCs, the most abundant stromal cells in PDAC, are resident pancreatic cells that undergo phenotypic changes upon activation, driving tumor progression through the secretion of cytokines, growth factors, ECM components (e.g., collagen, hyaluronic acid, fibronectin), and matrix metalloproteinases. In addition to cellular elements, ECM components significantly contribute to cancer aggressiveness by forming a physical barrier that hinders drug penetration, activating signaling pathways through specific receptor interactions, and generating peptides originating from the fragmentation of proteins to induce cancer migration. Regarding their critical roles in tumor progression, therapeutic approaches targeting PSCs and the ECM have garnered increasing interest in recent years. However, PSCs and stromal components may exhibit dual roles, with the potential to both promote and suppress tumor progression under different conditions. Therefore, targeting PSCs or stroma may lead to unintended outcomes, including exacerbation of cancer aggressiveness.

This review focuses on the multifaceted roles of PSCs in PDAC, particularly their interactions with cancer cells and their contributions to therapy resistance. Additionally, we discuss current and emerging therapeutic strategies targeting PSCs and the ECM components, including both preclinical and clinical efforts.

By synthesizing insights from recent literature, this review provides a comprehensive understanding of the role of PSCs in PDAC pathobiology and highlights potential therapeutic approaches targeting PSCs or ECM components to improve patient outcomes.

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.

Cancer cell survival and proliferation are correlated with increased metabolic activity and consequent oxidative stress, driving metabolic shifts that interfere with the immune response to malignant cells. This is the case of high-energy-demanding angioimmunoblastic T cell lymphoma (AITL), a highly aggressive cancer with poor survival rates, where malignant CD4+ PD-1high T cells show increased mitochondrial activity and Reactive oxygen species (ROS) accumulation. Here, we report that administration of ROS scavenging cerium oxide (CeO2) nanoparticles in an AITL preclinical mouse model leads to their preferential accumulation in the spleen, where the CD4+ PD-1high T cells driving malignancy were significantly reduced. This was accompanied by activation of previously exhausted cytotoxic CD8+ T cells, restoring their potent antitumor function. As a result, survival rates dramatically increase with no observed toxicity to healthy cells or tissues. Overall, it highlights the correlation between increased energy demand, increased mitochondrial mass, increased PD-1 expression, increased ROS production, and immune suppression and how this vicious loop can be stopped by scavenging ROS.

Hepatocellular carcinoma (HCC) is a severe disease associated with a poor prognosis. The role of aberrant lipid metabolism in the development and progression of HCC necessitates detailed characterization. Sterol regulatory element‑binding proteins (SREBPs), pivotal transcription factors governing lipogenesis, are central to this process. The present study aimed to assess the regulation of HCC by the SREBP signaling pathway, examining the expression levels of genes in this pathway, the clinical implications and its prognostic value using the Kaplan‑Meier method. Pearson's correlation coefficient was used to identify the co‑expression of SREBP pathway genes in HCC. Genomic analysis examined the frequency of TP53 mutations in groups with and without SREBP pathway alterations. In addition, small interfering RNAs targeting genes of the SREBP pathway were transfected into Huh‑7 and HCC‑LM3 cell lines. Subsequently, Cell Counting Kit‑8 and Transwell assays were carried out to evaluate the viability and invasion of these cells. Reverse transcription‑quantitative PCR and western blotting were performed to investigate the expression of TP53 in response to silencing of SREBP pathway genes. Dysregulation of SREBP pathway genes was detected in HCC tissues compared with in normal liver tissues, and predicted a poor prognosis. Silencing these genes reduced the viability and invasion of HCC cells. Furthermore, abnormal SREBP pathway gene expression was associated with poor survival rates, vascular invasion, advanced tumor stage and an increased incidence of TP53 mutations. By contrast, knockdown of SREBP pathway genes decreased mutant TP53 expression at both the mRNA and protein levels in HCC cells. The findings of the present study suggested that SREBP pathway genes could serve as promising prognostic biomarkers for HCC. The combined analysis of individual gene expression levels offers offer novel insights into the pathogenesis and progression of HCC.

Recurrence of breast cancer may be due to the presence of breast cancer stem cells (BCSC). Abnormal tumor cell growth is closely associated with increased reactive oxygen species (ROS) and disruption of redox homeostasis, and BCSCs exhibit low levels of ROS. The detailed mechanism between the low levels of ROS in BCSCs and their maintenance of stemness characteristics has not been reported. A growing number of studies have shown that tumor development is often accompanied by metabolic reprogramming, which is an important hallmark of tumor cells. As the first rate-limiting enzyme of pentose phosphate pathway (PPP), the expression of G6PD is precisely regulated in tumor cells, and there is a certain correlation between PPP and BCSCs. MiR-375 has been shown to inhibit stem cell-like properties in breast cancer, but the exact mechanism is not clear. Here, KLF5, as a transcription factor, was identified to bind to the promoter of G6PD to promote its expression, whereas miR-375 inhibited the expression of KLF5 by binding to the 3'UTR region of KLF5 mRNA and thus reduced the expression of G6PD expression, inhibits PPP to reduce NADPH, and increases ROS levels in breast cancer cells, thereby weakening breast cancer cell stemness. Our study reveals the specific mechanism by which miR-375 targets the KLF5/G6PD signaling axis to diminish the stemness of breast cancer cells, providing a therapeutic strategy against BCSCs.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

Studies have shown that the colonisation of active microorganisms is more conducive to the development of tumour immunotherapy, but intuitive evidence regarding shaping of the tumour immune microenvironment is lacking. In this study, we used Bifidobacterium longum subsp. longum (XZ01) to intervene in a colon cancer mouse model and found that its mechanism may be related to the interaction between the spatial distribution of microorganisms and tumour immunity. Through the visualisation method we established, for the first time, we showed that harmful active bacteria such as Streptococcus and Rhodococcus specifically accumulate in the middle and upper layers of tumour tissue. These bacteria likely participate in signalling pathways that affect macrophages by directly contacting or invading the macrophages, leading to a nondifferentiated state in macrophages and the loss of some immune functions. Furthermore, the accumulation of Streptococcus and Rhodococcus fragments in the deep layer of tumour tissue likely upregulates the expression of IL-10 in tumour tissue and inhibits other immune cells, such as CD8+ T cells, DC and NK cells. In contrast, XZ01 can specifically compete for the growth sites of Streptococcus and Rhodococcus in the middle and upper layers of tumour tissue and probably protects macrophages from being invaded by harmful bacteria. XZ01 directly regulates the polarisation of M0 macrophages towards the M1 phenotype by upregulating IFN-γ, thus activating tumour immunity to inhibit the growth of tumour cells. This study revealed that the influence of active microorganisms on the tumour immune microenvironment is crucial for effective immunotherapy intervention, potentially offering new targets for improving patient prognosis.

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.

Rheumatoid arthritis (RA) is a complex chronic autoimmune disease that remains incurable for most patients. With advances in our understanding of the disease's natural history, the concept of pre-RA has emerged as a window of opportunity to intervene before irreversible joint damage occurs. Numerous studies have indicated that the key step driving autoimmunity in early pre-RA lies at an extra-articular site, which is closely related to the regulatory T (Treg) cell-established immune tolerance to the gut microbiota. The intricate immunometabolic crosstalk between Treg cells and the gut microbiota is beginning to be understood, with the re-recognition of Treg cells as metabolic sensors in recent years. In the future, deciphering their immunometabolic dialogue may help to elucidate the underlying mechanisms of pre-RA. Identifying novel biological pathways in the pre-RA stage will bring insights into restoring immune tolerance, thereby potentially curing or preventing the onset of RA.

The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition-activated tumor cells and matrix metallopeptidase 11 (MMP-11)+ cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.

The balance between CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) plays a crucial role in the immune checkpoint inhibition (ICI) therapy in gastric carcinoma (GC). However, related factors leading to the disturbance of TME and resistance to ICI therapy remain unknown. In this study, we applied N6-methyladenosine (m6A) small RNA Epitranscriptomic Microarray and screened out 3'tRF-AlaAGC based on its highest differential expression level and lowest inter-group variance. N6-methyladenosine modification significantly enhanced the stability of 3'tRF-AlaAGC, which strengthened glycolysis and lactic acid (LA) production in GC cells by binding to PTBP1 (Polypyrimidine Tract Binding Protein 1). In the peritoneal GC implantation model established in huPBMC-NCG mice, 3'tRF-AlaAGC significantly increased the proportion of PD1+ Treg cells. Furthermore, in high-LA environments driven by glucose consumption of GC cells, Treg cells actively uptake LA through MCT1, facilitating NFAT1 translocation into the nucleus and enhancing PD1 expression, whereas PD1 expression by effector T cell is diminished. Meanwhile, T cell suppression assays were performed under low-LA or high-LA conditions, and the proliferation of CD8+ T cells was dampened by adding Sintilimab in a high-LA but not in a low-LA environment, suggesting the preferential activation of PD1+ Treg cell. These findings deciphered the complexities of the immune microenvironment in GC, providing prospects for identifying robust biomarkers that could improve the evaluation of therapeutic effectiveness and prognosis in immune therapy for GC.

Although immunotherapy has revolutionized clinical cancer treatment, the efficacy is limited due to the lack of tumor-associated antigens (TAAs) and the presence of compensatory immune checkpoints. To overcome the deficiency, a nano-system loaded with ozone and CD47 inhibitor RRx-001 is designed and synthesized. Upon irradiation, reactive oxygen species (ROS) generated from ozone reacts with nitric oxide (NO) metabolized from RRx-001 to form reactive nitrogen species (RNS), which presents a much stronger cell-killing ability than ROS. Molecular mechanism studies further reveal that RNS induce extensive immunogenic cell death (ICD). The released TAAs promote infiltration of cytotoxic T lymphocytes, which provides the basis for immune checkpoint blockade (ICB) therapy. Meanwhile, RRx-001 carried by the nanoparticles and the produced radicals repolarize M2-type tumor-associated macrophages (TAMs) into the anti-tumor M1-type, consequently reversing the immunosuppressive tumor microenvironment (TME). In a xenograft triple-negative breast cancer (TNBC) animal model, O3-001@lipo (liposome enwrapping O3 and RRx-001) plus irradiation shows a significant anti-tumor efficacy by improving cytotoxic lymphocyte infiltration and regulating immunosuppressive TME. In summary, the O3-001@lipo nano-system triggered by irradiation potently improves the efficacy of immunotherapy by introducing strong cytotoxic RNS, which not only enriches the toolbox of ICD inducer but also provides a strategy of treatment for immune deficient tumor. STATEMENT OF SIGNIFICANCE: This study introduces a nano-system that leverages ozone and RRx-001 in the presence of X-ray irradiation to generate reactive nitrogen species, enhancing immunogenic cell death and promoting T-lymphocyte infiltration in triple-negative breast cancer, addressing a significant unmet need in the field. The scientific contribution is the development of a clinically translatable nano-system that not only induces ICD but also reshapes the tumor microenvironment, which is expected to have a profound impact on the readership in pharmaceutics, material science, and nano-bio interaction, particularly for those interested in advanced immune therapy approaches.

Chemotherapy combined with checkpoint blockade antibodies targeting programmed cell death protein (PD-1) has achieved remarkable success in non-small cell lung cancer. However, few patients benefit from long-term treatment. Therefore, biomarkers capable of guiding the optimal therapeutic selection and reducing unnecessary toxicity are of pressing importance. In our research, we gathered serial blood samples from two groups of non-small cell lung cancer patients: 49 patients received a combination of therapies, and 34 patients went under chemotherapy alone. Utilizing non-targeted metabolomic analysis, we examined different metabolites' disparity. Among the lot, L-phenylalanine emerged as a significant prognostic marker in the combination treatment of non-small cell lung cancer patients, interestingly absent in patients under sole chemotherapy. The reduced ratio of L-phenylalanine concentration (two-cycle treatment vs. pre-treatment) was associated with improved progression-free survival (hazard ratio = 1.8000, 95% confidence interval: 0.8566‒3.7820, p < 0.0001) and overall survival (hazard ratio = 1.583, 95% confidence interval: 0.7416‒3.3800, p < 0.005). We further recruited two validation cohorts (cohort 1: 40 patients and cohort 2: 30 patients) to validate the sensitivity and specificity of L-phenylalanine prediction. Our results demonstrate that a model based on L-phenylalanine variations could serve as an early risk-assessment tool for non-small cell lung cancer patients undergoing treatment, potentially facilitating strategic clinical decision-making.

Sonodynamic therapy (SDT) is a promising therapeutic modality known for its non-invasiveness, temporal-spatial controllability, and deeper tissue penetration. However, the SDT treatment efficacy is still hampered by the scarcity of ideal sonosensitizers and complex tumor microenvironment (TME). To address these challenges, a sono-metabolic nano-composite (TiO2-Au@DON) using the metabolic reprogramming prodrugs of 6-Diazo-5-oxo-l-norleucine (DON) grafted on TiO2-Au Janus nanoparticles (NPs) is fabricated. The coupling of TiO2 and gold in the TiO2-Au@DON effectively prevents the fast recombination of excited electrons and holes under ultrasound irradiation. The result is the generation of higher levels of both type I and II reactive oxygen species (ROS) compared to pure TiO2, which helps overcome the limitations of SDT in the hypoxic TME. Furthermore, the TiO2-Au Janus NPs act as nano-carriers, delivering DON prodrugs to the tumor site. The released DON can disrupt nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and tumor redox homeostasis by reprogramming the metabolic pathways while it intensifies the activities of immune cells. This metabolic disruption amplifies SDT-mediated oxidative stress, resulting in the increase of tumor sensitivity to ROS through TiO2-Au@DON-integrated synergistic effects of SDT and glutamine reprogramming strategies. This increased sensitivity ultimately induces robust immunogenic cell death (ICD), enhancing antitumor therapeutic efficacy and remodeling the tumor's immunosuppressive microenvironment.

The host immune system is adapted in a variety of ways by tumour microenvironment and growing tumour interacts to promote immune escape. One of these adaptations is manipulating the metabolic processes of cells in the tumour microenvironment. The growing tumour aggressively utilise glucose, its primary energy source available in tumour site, and produce lactate by Warburg effect. In such a hostile environment, tumour-infiltrating immune cells are unable to survive metabolically. Tumour-infiltrating CD4+ Treg cells, on the other hand, adapted to an alternative energy-generating system, switching from the highly-competitive glucose to the fatty-acid metabolic pathway, by down-regulating glucose-metabolising genes and up-regulating fatty-acid metabolising genes. Tregs with high-levels of the fatty acid scavenger receptor CD36, a key component of the fatty-acid metabolic pathway, aided this metabolic shift. Treg cell formation was hampered when the fatty-acid metabolic pathway was disrupted, showing that it is necessary for Treg cell development. FOXP3, the Treg lineage-specific transcription factor, regulates fatty-acid metabolism by inducing CD36 transcription. A high-fat diet enhanced Treg development while suppressing anti-tumour immunity, whereas a low-fat diet suppressed Treg development. The altered metabolism of tumour-infiltrating Treg cells enables their rapid generation and survival in the hostile tumour microenvironment, aiding cancer progression. Fascinatingly, mice fed with a low-fat diet showed a positive prognosis with chemotherapy than mice fed with a high-fat diet. Thus, a maximum efficacy of chemotherapy might be achieved by altering diet composition during chemotherapy, providing a promising indication for future cancer treatment.

Fructose-1,6-bisphosphatase 1 (FBP1) is a key gluconeogenic enzyme that plays complex and context-dependent roles in cancer biology. This review comprehensively examines FBP1's dual functions as both a tumor suppressor and an oncogene across various cancer types. In many cancers, such as hepatocellular carcinoma, clear cell renal cell carcinoma, and lung cancer, downregulation of FBP1 contributes to tumor progression through metabolic reprogramming, promoting glycolysis, and altering the tumor microenvironment. Conversely, in certain contexts like breast and prostate cancers, FBP1 overexpression is associated with tumor promotion, indicating its oncogenic potential. The review explores FBP1's interactions with immune cells within the tumor microenvironment, influencing immune surveillance and tumor immune escape mechanisms. Additionally, FBP1 emerges as a promising diagnostic and prognostic biomarker, with expression levels correlating with patient outcomes in multiple cancers. Future therapeutic strategies targeting FBP1 are discussed, including inhibitors, activators, epigenetic modulation, and combination therapies, while addressing the challenges posed by its dual nature. Understanding the multifaceted roles of FBP1 offers valuable insights into cancer metabolism and opens avenues for personalized therapeutic interventions.

Higher and richer nutrient requirements are typical features that distinguish tumor cells from AU: cells, ensuring adequate substrates and energy sources for tumor cell proliferation and migration. Therefore, nutrient deprivation strategies based on targeted technologies can induce impaired cell viability in tumor cells, which are more sensitive than normal cells. In this review, nutrients that are required by tumor cells and related metabolic pathways are introduced, and anti-tumor strategies developed to target nutrient deprivation are described. In addition to tumor cells, the nutritional and metabolic characteristics of other cells in the tumor microenvironment (including macrophages, neutrophils, natural killer cells, T cells, and cancer-associated fibroblasts) and related new anti-tumor strategies are also summarized. In conclusion, recent advances in anti-tumor strategies targeting nutrient blockade are reviewed, and the challenges and prospects of these anti-tumor strategies are discussed, which are of theoretical significance for optimizing the clinical application of tumor nutrition deprivation strategies.

Radiotherapy is a cornerstone of lung cancer management, though its efficacy is frequently undermined by intrinsic and acquired radioresistance. This review examines the complexity of lung tumors, highlighting their potential as a reservoir of novel targets for radiosensitization. Ionizing radiation (IR) primarily exerts its effects through oxidative damage and DNA double-strand breaks (DSBs). Lung cancer cells, however, develop mutations that enhance DNA damage response (DDR) and suppress cell death pathways. Additionally, interactions between tumor cells and tumor microenvironment (TME) components-including immune cells, stromal cells, and molecular mediators such as cytokines, chemokines, and growth factors-contribute to resistance against IR. Understanding these intricate relationships reveals potential targets to improve radiotherapy outcomes. Promising targets include DDR pathways, immunosuppressive cells and molecules, hypoxia, proangiogenic mediators, and other key signaling pathways. This review discusses emerging strategies, such as combining radiotherapy with immunomodulators, hypoxia and proangiogenic inhibitors, DDR-targeting agents, and other innovative approaches. By offering a comprehensive analysis of the lung TME, this review underscores opportunities to enhance radiotherapy effectiveness through targeted radiosensitization strategies.

Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

The COVID-19 pandemic has led to widespread long-term complications, known as post-COVID conditions (PCC), particularly affecting vulnerable populations such as cancer patients. This study aims to predict the incidence of PCC in hospitalised cancer patients using the data from a longitudinal cohort study conducted in four major university hospitals in Moscow, Russia.

Clinical data have been collected during the acute phase and follow-ups at 6 and 12 months post-discharge. A total of 49 clinical features were evaluated, and machine learning classifiers including logistic regression, random forest, support vector machine (SVM), k-nearest neighbours (KNN), and neural network were applied to predict PCC.

Model performance was assessed using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. KNN demonstrated the highest predictive performance, with an AUC of 0.80, sensitivity of 0.73, and specificity of 0.69. Severe COVID-19 and pre-existing comorbidities were significant predictors of PCC.

Machine learning models, particularly KNN, showed some promise in predicting PCC in cancer patients, offering the potential for early intervention and personalised care. These findings emphasise the importance of long-term monitoring for cancer patients recovering from COVID-19 to mitigate PCC impact.

The immune system must carefully balance fighting pathogens with minimization of inflammation and avoidance of autoimmune responses. Over the past ten years, researchers have extensively studied the mechanisms regulating this delicate balance. Comprehending these mechanisms is essential for developing treatments for inflammatory conditions.

This review aims to synthesize knowledge of immunoregulatory processes published from 2014-2024 and to highlight discoveries that provide fresh perspectives on this complex balance.

The keywords "molecular mechanisms", "immune regulation", "immune signaling pathways", and "immune homeostasis" were used to search PubMed for articles published between 2014 and 2024, with a preference for articles published in the past three years.

Recent research has pinpointed the impact of factors such as cytokine signaling, T-cell regulation, epigenetic regulation, and immunometabolism on immune function.

New research highlights the intricate interactions between the immune system and other molecular elements. A key area of interest is the impact of non-coding RNAs and metabolic pathways on the regulation of immune responses.

Exploring the mechanisms by which the immune system is regulated will provide new avenues for developing treatments to address autoimmune and inflammatory conditions.

Pyruvate Kinase Muscle Isozyme (PKM), as a member of the pyruvate kinase, is a key enzyme in glycolysis. Numerous tumors have demonstrated its oncogenic properties. There is, however, no pan-carcinogenic analysis for PKM.

A thorough analysis of PKM across various types of cancer was carried out using bioinformatics resources like The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) database. This study involved analyzing the role of PKM in 33 various types of cancers, along with investigating gene expressions, survival rates, clinical importance, genetic changes, immune system presence, and related signaling pathways. Furthermore, we evaluated the effects of PKM knockdown on human colon carcinoma, and glioblastoma cell lines by in vitro experimentation.

In most tumors, PKM expression was markedly increased and was associated with unfavorable overall survival (OS) in certain individuals. In addition, infiltration of macrophages was associated with PKM expression in various tumors. PKM was linked to glycolysis/gluconeogenesis, HIF-1 signaling, carbon metabolism, and NADPH regeneration in a mechanistic manner. Additionally, cell experiments showed that the knockdown of PKM could reduce the proliferation and migration abilities while promoting the apoptosis of Caco-2, and U-87 MG cells.

PKM controls immune cell infiltration, impacts patient outcomes in various types of cancer, and plays an essential role in proliferation and migration in some tumor cells by affecting glycometabolism. The PKM molecule may serve as a potential prognostic biomarker and therapeutic target for human cancers.

Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies globally, characterized by significant heterogeneity, late-stage diagnosis, and resistance to treatment. In recent years, the advent of immune-checkpoint blockades (ICBs) and targeted immune cell therapies has marked a substantial advancement in HCC treatment. However, the clinical efficacy of these existing therapies is still limited, highlighting the urgent need for new breakthroughs. Natural killer (NK) cells, a subset of the innate lymphoid cell family, have shown unique advantages in the anti-tumour response. With increasing evidence suggesting the crucial role of dysfunctional NK cells in the pathogenesis and progression of HCC, considerable efforts have been directed toward exploring NK cells as a potential therapeutic target for HCC. In this review, we will provide an overview of the role of NK cells in normal liver immunity and in HCC, followed by a detailed discussion of various NK cell-based immunotherapies and their potential applications in HCC treatment.

The convergence of macrophage-targeted strategies with immune checkpoint blockade therapies defines a pivotal avenue in contemporary tumor therapy. Identifying robust genetic regulators in this context is imperative.

This study elucidates IFI30's role in enhancing Major Histocompatibility Complex II (MHC-II) restriction antigen processing. Despite its recognition in cancer immunotherapy, IFI30 remains a nascent focus. Our approach involves a multi-omics analysis of IFI30 tumor immunological profile in the macrophage-mediated Tumor Microenvironment (TME), spanning various cancers and bolstered by rigorous co-culture laboratory work.

IFI30 predominantly localizes in monocyte/macrophage populations, correlating strongly with immune cell infiltration. Substantiated by single-cell analysis, IFI30 exhibits significant functional enrichment in immune-related pathways. Co-expression with immune-related genes, including MHC elements and immune checkpoints, further validates its relevance.

Our study positions IFI30 as a promising immunotherapeutic target. Pan-cancer analyses and glioblastoma multiforme (GBM) investigations collectively underscore IFI30's potential as a TME modulator, particularly in its interaction with M2-macrophages. IFI30 emerges as a prospective intervention point in the immunotherapeutic landscape.

Our study aims to investigate the role of pyrimidine metabolism in prostate cancer and its associations with the immune microenvironment, drug sensitivity, and tumor mutation burden. Through transcriptomic and single-cell RNA sequencing analyses, we explored metabolic pathway enrichment, immune infiltration patterns, and differential gene expression in prostate cancer samples. The results showed that pyrimidine metabolism-related genes were significantly upregulated in the P2 subgroup compared to the P1 subgroup, with enhanced metabolic activity observed in basal and luminal epithelial cells. In addition, immune infiltration analysis revealed a strong correlation between pyrimidine metabolism and immune cell regulation, particularly involving T cell activity. Tumors in the P2 subgroup, characterized by higher pyrimidine metabolism, exhibited greater infiltration of activated CD4 + T cells and M2 macrophages, indicating a potential link between metabolic reprogramming and the immune response in prostate cancer. Drug sensitivity analysis further demonstrated that tumors with elevated pyrimidine metabolism displayed increased responsiveness to several chemotherapeutic agents, including BI-2536, JW-7-24-1, and PAC-1, suggesting that targeting pyrimidine metabolism may enhance treatment efficacy. Moreover, key genes involved in pyrimidine de novo synthesis, such as RRM2, were identified as potential drivers of tumor progression, providing new insights into the molecular mechanisms underlying aggressive prostate cancer phenotypes. In conclusion, pyrimidine metabolism plays a critical role in prostate cancer progression, influencing immune infiltration and drug sensitivity. Targeting this metabolic pathway offers a promising strategy for the development of new therapeutic approaches, particularly for overcoming drug resistance and improving outcomes in patients with advanced prostate cancer.