Lactate and lactylation in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Language: Английский

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Metabolism/Immunity Dual‐Regulation Thermogels Potentiating Immunotherapy of Glioblastoma Through Lactate‐Excretion Inhibition and PD‐1/PD‐L1 Blockade

Advanced Science, Journal Year: 2024, Volume and Issue: 11(18)

Published: March 9, 2024

Abstract Intrinsic immunosuppressive tumor microenvironment (ITM) and insufficient infiltration of T cells severely impede the progress glioblastoma (GBM) immunotherapy. In this study, it is identify that inhibiting expression glucose transporter 1 (GLUT1) can facilitate prevention lactate excretion from glycolysis, which significantly alleviates lactate‐driven ITM by reducing tumor‐associated macrophages (TAMs) regulatory (Tregs). Simultaneously, findings show generated inflammatory cytokine IFN‐γ during immune activation aggravates escape upregulating checkpoint programmed death‐ligand (PD‐L1) in TAMs. Therefore, an injectable thermogel loaded with a GLUT1 inhibitor BAY‐876 PD‐1/PD‐L1 blocker BMS‐1 (Gel@B‐B) for dual‐regulation metabolism immunity GBM developed. Consequently, situ injection Gel@B‐B delays growth prolongs survival orthotopic mouse model. By actively exposing antigens to antigen‐presenting cells, vaccine combined found increase fraction effector (Th1/CTLs) microenvironment, thereby remarkably mitigating recurrence long‐term. This study may provide promising strategy

Language: Английский

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Glycolysis in the tumor microenvironment: a driver of cancer progression and a promising therapeutic target

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: June 12, 2024

Even with sufficient oxygen, tumor cells use glycolysis to obtain the energy and macromolecules they require multiply, once thought be a characteristic of known as "Warburg effect". In fact, throughout process carcinogenesis, immune stromal cells, two major cellular constituents microenvironment (TME), also undergo thorough metabolic reprogramming, which is typified by increased glycolysis. this review, we provide full-scale review glycolytic remodeling several types TME show how these behave in acidic milieu created glucose shortage lactate accumulation result Notably, an overview putative targets inhibitors along viability using combination immunotherapy chemotherapy. Understanding situations diverse within immunological will aid creation subsequent treatment plans.

Language: Английский

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Recent Advances in Biomimetic Strategies for the Immunotherapy of Glioblastoma

Biomaterials, Journal Year: 2024, Volume and Issue: 311, P. 122694 - 122694

Published: June 28, 2024

Language: Английский

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Silencing BMAL1 promotes M1/M2 polarization through the LDHA/lactate axis to promote GBM sensitivity to bevacizumab

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 134, P. 112187 - 112187

Published: May 11, 2024

Language: Английский

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Identification of ferroptosis-related LncRNAs as potential targets for improving immunotherapy in glioblastoma

Computer Methods in Biomechanics & Biomedical Engineering, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: Jan. 1, 2025

The effect of ferroptosis-related long non-coding RNAs (lncRNAs) in predicting immunotherapy response to glioblastoma (GBM) remains obscure. This study established a 11-lncRNAs prognostic signature. Differential gene expression analysis, univariate and multivariate Cox regression analyses the least absolute shrinkage selection operator (LASSO) algorithm were used identify genes establish nomogram model risk score. Kaplan-Meier survival plots receiver operating characteristic (ROC) curve analysis evaluate accuracy TCGA-GBM cohort. To verify these signatures, we analyzed levels three lncRNAs (AGAP2-AS1, OSMR-AS1, UNC5B-AS1) LN229 U87 cells. ROC showed that area under (AUC) this signature is 0.814, suggesting it has promising performance on GBM prediction. rate patients high-risk group was significantly lower than low-risk group, prediction superior conventional clinicopathological factors. Further qRT-PCR experiment also confirmed our lncRNA signatures. These might be therapeutic targets for glioblastoma, targeting can improve efficacy immunotherapy, especially immune checkpoint inhibitors. Mechanistically, findings attribute N6-methyladenosine (m6A) mRNA modification lncRNAs.

Language: Английский

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Glucose Metabolism‐Targeted Poly(amino acid) Nanoformulation of Oxaliplatin(IV)‐Aspirin Prodrug for Enhanced Chemo‐Immunotherapy

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Inappropriate glucose metabolism in cancer cells is associated with immunosuppressive tumor microenvironments (TMEs). Although glycolysis inhibition enhances T cell-mediated immune responses, the integrated platforms combining immunotherapy remain underdeveloped. To address this gap, a metabolism-targeted poly(amino acid) nanoformulation of oxaliplatin(IV)-aspirin prodrug (NP/OXA-ASP2) developed to improve chemo-immunotherapy by suppressing glycolysis. This nanoparticle exhibits selective release, discharging 90.0% OXA-ASP2 under reductive conditions within 36 h. Furthermore, over 80% converts OXA and ASP 12 h, promoting mitochondrial damage inhibition, which amplifies immunogenic cell death induced OXA. In addition, glycolytic flux reduces lactate leakage, mitigating TMEs. Together, these mechanisms contribute stronger efficacy. Compared plus formulation, NP/OXA-ASP2 demonstrates superior performances, reducing levels at site 25.4%, increasing proportion cytotoxic lymphocytes 1.53 times, decreasing regulatory 2.20 improving 1.39-fold rate. These findings underscore that promising platform for integrating metabolic regulation immunomodulation holds significant potential advancing clinical chemo-immunotherapy.

Language: Английский

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Targeting metabolic reprogramming in glioblastoma as a new strategy to overcome therapy resistance

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 26, 2025

Glioblastoma (GBM) is one of the deadliest tumors due to its high aggressiveness and resistance standard therapies, resulting in a dismal prognosis. This lethal tumor carries out metabolic reprogramming order modulate specific pathways, providing metabolites that promote GBM cells proliferation limit efficacy treatments. Indeed, remodels glucose metabolism undergoes Warburg effect, fuelling glycolysis even when oxygen available. Moreover, recent evidence revealed rewiring nucleotide, lipid iron metabolism, not only an increased growth, but also radio- chemo-resistance. Thus, while on hand advantage for GBM, other it may represent exploitable target hamper progression. Lately, number studies focused drugs targeting uncover their effects therapy resistance, demonstrating some these are effective, combination with conventional treatments, sensitizing radiotherapy chemotherapy. However, heterogeneity could lead plethora alterations among subtypes, hence treatment might be effective proneural mesenchymal ones, which more aggressive resistant approaches. review explores key mechanisms involvement highlighting how acts as double-edged sword taking into account pathways seem offer promising options GBM.

Language: Английский

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Single-cell and spatial transcriptomic insights into glioma cellular heterogeneity and metabolic adaptations

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 4, 2025

Glioblastoma, one of the most aggressive and heterogeneous malignant tumors, presents significant challenges for clinical management due to its cellular metabolic complexity. This review integrates recent advancements in single-cell RNA sequencing (scRNA-seq) spatial transcriptomics elucidate glioblastoma’s heterogeneity reprogramming. Diverse subpopulations, including proliferative cells, stem-like mesenchymal-like immune-related contribute tumor progression, treatment resistance, microenvironmental interactions. Spatial has further revealed distinct distributions these highlighting differences activities between core periphery. Key adaptations, such as enhanced glycolysis, fatty acid oxidation, glutamine metabolism, play critical roles supporting growth, immune evasion, therapeutic resistance. Targeting pathways, especially combination with immunotherapy, represents a promising avenue glioblastoma treatment. emphasizes importance integrating multi-omics technologies decode landscape explore novel strategies. By addressing current challenges, redundancy spatiotemporal dynamics, this work provides insights into advancing precision medicine glioblastoma.

Language: Английский

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Remodeling of Effector and Regulatory T Cells by Capture and Utilization of miRNAs Using Nanocomposite Hydrogel for Tumor-Specific Photothermal Immunotherapy

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

In immunotherapy for malignant tumors, the dysregulation of balance between effector T cells and regulatory (Tregs) uncertain efficacy due to individual differences have been considered as two critical challenges. this study, we engineered an injectable nanocomposite hydrogel system (SNAs@M-Gel) capable suppressing Treg proliferation blocking PD-1/PD-L1-mediated immune evasion effectively, achieved through stimulus-responsive modulation multiple tumor-associated microRNAs. Simultaneously, enables microRNA-dependent photothermal immunotherapy, facilitating a highly efficient personalized approach tumor treatment. Specifically, oxidized sodium alginate (OSA) cancer cell membrane (CCM)-encapsulated spherical nucleic acid nanoparticles (SNAs@M) were used construct SNAs@M-Gel in situ at site formation pH-sensitive Schiff base bonding cross-linking using endogenous calcium ions (Ca2+). During treatment, was retained locally up 10 days, SNAs@M continuously released into microenvironment. Through targeting ability CCM, precisely entered specifically hybridized with overexpressed miR-214 miR-130a, leading significant downregulation PD-L1 expression on restoration cytotoxic lymphocyte (CTL) function suppressed by Tregs, thereby remodeling addition, miRNAs functioned agents, aggregation SNAs allowing localized production agents directly inside cells, which, under near-infrared (NIR) irradiation, promoted selective therapy. This cascade events not only led destruction primary but also resulted release substantial number tumor-related antigens, which triggered maturation adjacent dendritic (DCs) subsequent priming tumor-specific CTLs, while simultaneously depleting reversing tumor-promoting microenvironment enhancing overall therapeutic immunotherapy.

Language: Английский

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