The future of cancer immunotherapy: microenvironment-targeting combinations

Cell Research, Journal Year: 2020, Volume and Issue: 30(6), P. 507 - 519

Published: May 28, 2020

Abstract Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies primary and secondary resistance immunotherapy are multifaceted, deriving not from tumor intrinsic factors, also complex interplay between cancer its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories approaches design novel drugs combination therapies: first involves direct modification tumor, while second indirectly enhances immunogenicity through alteration By systematically factors that mediate resistance, able identify mechanistically-driven improve outcomes.

Language: Английский

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Manipulating Intratumoral Fenton Chemistry for Enhanced Chemodynamic and Chemodynamic‐Synergized Multimodal Therapy

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(48)

Published: Sept. 27, 2021

Chemodynamic therapy (CDT) uses the tumor microenvironment-assisted intratumoral Fenton reaction for generating highly toxic hydroxyl free radicals (•OH) to achieve selective treatment. However, limited efficiency restricts therapeutic efficacy of CDT. Recent years have witnessed impressive development various strategies increase reaction. The introduction these reinforcement can dramatically improve treatment CDT and further promote enhanced (ECDT)-based multimodal anticancer treatments. In this review, authors systematically introduce strategies, from their basic working principles, mechanisms representative clinical applications. Then, ECDT-based is discussed, including how integrate emerging accelerating therapy, as well synergistic ECDT other methods. Eventually, future direction challenges therapies are elaborated, highlighting key scientific problems unsolved technical bottlenecks facilitate translation.

Language: Английский

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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(9), P. 5289 - 5335

Published: April 22, 2021

The major facilitator superfamily (MFS) is the largest known of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum substrates, either down their concentration gradient or uphill using energy stored in electrochemical gradients. Over last 10 years, more than hundred different transporter structures covering close to 40 members have provided an atomic framework piecing together molecular basis transport cycles. Here, we summarize remarkable promiscuity terms substrate recognition and proton coupling as well intricate gating mechanisms undergone achieving translocation. We outline studies that show how residues far from binding site can be just important fine-tuning specificity those directly coordinating substrate, number evolved form unique complexes with chaperone signaling functions. Through deeper mechanistic description glucose (GLUT) multidrug resistance (MDR) antiporters, novel refinements rocker-switch alternating-access model, such latch mechanism proton-coupled monosaccharide transport. emphasize full understanding requires elucidation dynamics, landscapes, determination rate transitions modulated by lipids.

Language: Английский

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Lactic Acid and an Acidic Tumor Microenvironment suppress Anticancer Immunity

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(21), P. 8363 - 8363

Published: Nov. 7, 2020

Immune evasion and altered metabolism, where glucose utilization is diverted to increased lactic acid production, are two fundamental hallmarks of cancer. Although has long been considered a waste product this alteration, it now well accepted that production the resultant acidification tumor microenvironment (TME) promotes multiple critical oncogenic processes including angiogenesis, tissue invasion/metastasis, drug resistance. We others have hypothesized excess in TME responsible for suppressing anticancer immunity. Recent studies support hypothesis provide mechanistic evidence explaining how acidic impede immune cell functions. In review, we consider acid’s role as immunoregulatory molecule involved effector proliferation inducing de-differentiation. This results inhibition antitumor responses activation potent, negative regulators innate adaptive cells. also an Finally, insights help translate new knowledge into impactful therapies.

Language: Английский

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HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(10), P. 5074 - 5087

Published: Sept. 1, 2020

Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis metabolic rewiring are well-established drivers of breast aggressiveness, therapy resistance, poor prognosis. Targeting HIF its downstream targets in metabolism has been unsuccessful so far clinical setting, with major unresolved challenges residing target selection, development robust biomarkers for response prediction, understanding harnessing escape mechanisms. This Review discusses pathophysiological role HIFs, angiogenesis, targeting these features patients cancer. Rational therapeutic combinations, especially immunotherapy endocrine therapy, seem most promising exploitation intricate interplay cells tumor microenvironment.

Language: Английский

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A proteogenomic portrait of lung squamous cell carcinoma

Cell, Journal Year: 2021, Volume and Issue: 184(16), P. 4348 - 4371.e40

Published: Aug. 1, 2021

Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape LSCC, providing deeper exposition LSCC biology potential implications. identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 overexpressing target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such LSD1 EZH2 to SOX2-overexpressing tumors. Our data support complex regulation metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related observations suggest directions further investigation. Proteogenomic dissection CDKN2A mutations argue more nuanced assessment RB1 protein expression phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation LUAD, HNSCC identified both unique common vulnerabilities. These proteogenomics resources may guide research into treatment LSCC.

Language: Английский

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Lactate in the tumour microenvironment: From immune modulation to therapy

EBioMedicine, Journal Year: 2021, Volume and Issue: 73, P. 103627 - 103627

Published: Oct. 15, 2021

Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in tumour microenvironment (TME). Excessive lactate secreted metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source shuttling between different cell populations, inhibiting mechanistic (previously 'mammalian') target rapamycin (mTOR) pathway cells. This review focuses on recent advances regulation well therapeutic strategies targeting anabolism transport TME, such those involving glycolytic enzymes monocarboxylate transporter inhibitors. Considering multifaceted roles metabolism, a comprehensive understanding how lactate-targeting therapies regulate TME will provide insights into complex relationships metabolism antitumour immunity.

Language: Английский

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Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates

Cell, Journal Year: 2020, Volume and Issue: 184(2), P. 370 - 383.e13

Published: Dec. 16, 2020

Language: Английский

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Hyaluronan: Metabolism and Function

Biomolecules, Journal Year: 2020, Volume and Issue: 10(11), P. 1525 - 1525

Published: Nov. 7, 2020

As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in organization tissue architecture and regulation cellular functions, such as cell proliferation migration, through interactions with cell-surface receptors binding molecules. Metabolic pathways for biosynthesis degradation tightly control turnover rate, concentration, molecular size tissues. Despite relatively simple chemical composition this polysaccharide, its wide range weights mediate diverse functions that depend on concentration. Genetic engineering pharmacological approaches have demonstrated close associations between metabolism many physiological pathological events, including morphogenesis, wound healing, inflammation. Moreover, emerging evidence has suggested accumulation matrix fragments due to altered expression synthases hyaluronidases potentiates cancer development progression by remodeling tumor microenvironment. In addition well-known exerted hyaluronan, recent metabolomic also revealed synthesis can regulate via reprogramming metabolism. This review highlights current advances knowledge catabolism describes associated

Language: Английский

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Lung Myofibroblasts Promote Macrophage Profibrotic Activity through Lactate-induced Histone Lactylation

American Journal of Respiratory Cell and Molecular Biology, Journal Year: 2020, Volume and Issue: 64(1), P. 115 - 125

Published: Oct. 19, 2020

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical their profibrotic phenotype. The primary byproduct, lactate, also secreted into the extracellular milieu, together with which and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast might have non-cell autonomous effect through lactate regulating pathogenic phenotype of alveolar macrophages. Here, demonstrated there was markedly increased conditioned media TGF-β1 (transforming growth factor-β1)-induced BAL fluids (BALFs) from mice TGF-β1- or bleomycin-induced fibrosis. Importantly, BALFs promoted mediator expression Mechanistically, induced histone lactylation promoters genes macrophages, consistent upregulation this epigenetic modification these cells lungs. inductions gene were mediated by p300, evidenced diminished concentrations p300-knockdown Collectively, our study establishes addition protein, lipid, nucleic acid molecules, metabolite can mediate intercellular regulations setting Our findings shed new light on mechanism underlying key contribution pathogenesis

Language: Английский

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