A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance DOI Creative Commons
Ginette S. Santiago-Sánchez, Kellsye P. Fabian, James W. Hodge

et al.

Cancer Biology & Therapy, Journal Year: 2024, Volume and Issue: 25(1)

Published: Feb. 2, 2024

The discovery of immune checkpoints and the development checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still high proportion patients who do not benefit from ICI therapy due to lack when first treated (primary resistance) or detection disease progression months after objective observed (acquired resistance). Here, we review current FDA-approved for treatment certain solid malignancies, evaluate contrasting responses blockade different types, explore known mechanisms associated with resistance (CBR), assess strategies field that seek overcome these mechanisms. In order improve therapies develop new ones, immunotherapy has an unmet need identifying other molecules act as checkpoints, uncovering promote CBR.

Language: Английский

Cancer stem cells: advances in knowledge and implications for cancer therapy DOI Creative Commons

Xianjing Chu,

Wentao Tian,

Jiaoyang Ning

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 5, 2024

Abstract Cancer stem cells (CSCs), a small subset of in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, maintain tumor heterogeneity. continues be significant global disease burden. In the past, surgery, radiotherapy, chemotherapy were main cancer treatments. The technology treatments develop advance, emergence targeted therapy, immunotherapy provides more options for patients certain extent. However, limitations efficacy treatment resistance still inevitable. Our review begins with brief introduction historical discoveries, original hypotheses, pathways regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, their crosstalk. We focus on role CSCs various therapeutic outcomes resistance, including how affect content alteration related molecules, CSCs-mediated clinical value targeting refractory, progressed or advanced tumors. summary, efficacy, method is difficult determine. Clarifying regulatory mechanisms biomarkers currently mainstream idea.

Language: Английский

Citations

110
VEGF signaling: Role in angiogenesis and beyond DOI
Pallab Shaw, Shailendra Kumar Dhar Dwivedi, Resham Bhattacharya

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(2), P. 189079 - 189079

Published: Jan. 26, 2024

Language: Английский

Citations

68
Cold and hot tumors: from molecular mechanisms to targeted therapy DOI Creative Commons
Bo Wu, Bo Zhang, Bowen Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 18, 2024

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment therapy, only a minority patients exhibit positive response to it. In with solid tumors, those who respond well typically demonstrate an active profile referred as "hot" (immune-inflamed) phenotype. On other hand, non-responsive may distinct "cold" (immune-desert) phenotype, differing from features tumors. Additionally, there is more nuanced "excluded" positioned between and categories, known type. Effective differentiation understanding intrinsic factors, characteristics, TME, external factors are critical for predicting results. It widely accepted that therapy exerts profound effect on limited efficacy against or "altered" necessitating combinations therapeutic modalities enhance cell infiltration into tissue convert tumors ones. Therefore, aligning traits this review systematically delineates respective influencing extensively discusses varied approaches drug targets based assess efficacy.

Language: Английский

Citations

68
Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy DOI Creative Commons

Mengke Niu,

Ming Yi, Yuze Wu

et al.

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Aug. 12, 2023

Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators antitumor immunity, like TGF-β VEGFA, are also involved escape tumor cells induce immunotherapy resistance.We developed novel anti-TGF-β/VEGF bispecific antibody Y332D based on Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting transwell assays were used measure biological activities anti-TGF-β moiety. NFAT luminescent viability assay tube formation anti-VEGF vivo efficacy or combination with PD-1 blockade was evaluated H22, EMT-6, 4T1, AKT/Ras-driven murine hepatocellular carcinoma models. Immunofluorescent staining, RNA-seq quantitative RT-PCR adopted analyze alterations microenvironment.Y332D could maintain specific binding affinities for VEGFA. almost entirely counteracted vitro functions including immunosuppression, activated signaling, epithelial-mesenchymal transition (EMT), VEGF/VEGFR HUVEC proliferation formation. experiment data demonstrated that more effective inhibiting growth metastasis than monotherapies. In therapies, plus exhibited most durable effect. Mechanistically, upregulated density function tumor-infiltrating lymphocytes reinvigorated immunity.Y332D simultaneously block VEGF signalings. comparison monotherapies, combined exerts superior through improving microenvironment.

Language: Английский

Citations

55
Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis DOI Creative Commons
Lei Wang, Wang‐Qing Liu, Sylvain Broussy

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 4, 2024

Vascular endothelial growth factors (VEGF), factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological pathological angiogenesis. In the last 20 years, many drugs have been developed based on VEGF/VEGFR treat diverse cancers retinopathies, new with improved properties continue emerge at fast rate. consist of different molecular structures characteristics, which enable them inhibit interaction VEGF/VEGFR, activity VEGFR tyrosine kinase (TK), or signaling. this paper, we reviewed development marketed involved axis, as well some important drug candidates clinical trials. We discuss mode action, benefits, current challenges that will need be addressed by next-generation drugs. focus characteristics each drug, including those approved only China.

Language: Английский

Citations

46
Targeting the tumour vasculature: from vessel destruction to promotion DOI
Sophie Guelfi, Kairbaan Hodivala‐Dilke, Gabriele Bergers

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(10), P. 655 - 675

Published: Aug. 29, 2024

Language: Английский

Citations

30
Hypoxia-inducible factor in cancer: from pathway regulation to therapeutic opportunity DOI Creative Commons
Brian Ortmann

BMJ Oncology, Journal Year: 2024, Volume and Issue: 3(1), P. e000154 - e000154

Published: Feb. 1, 2024

Cancer remains one of the most formidable challenges in modern medicine, due to its complex and dynamic nature, which demands innovative therapeutic approaches. One major challenge cancer treatment is tumour microenvironment particular hypoxia (low oxygen levels), contributes progression immune evasion. At cellular level, this primarily governed by hypoxia-inducible factor (HIF). HIF a transcription that orchestrates responses low levels, driving angiogenesis, metabolic adaptation regulation. HIF's dysregulation frequently observed various types correlates with increased aggressiveness, metastasis, resistance therapy poor patient prognosis. Consequently, understanding mechanisms underlying activation downstream effects has become crucial developing targeted therapies for improving outcomes represents key step towards precision medicine. Recent advancements drug development have led emergence inhibitors, aim disrupt HIF-driven processes providing benefit. Here, we provide review molecular through promotes growth resistance, emphasising potential clinical benefits HIF-targeted therapies. This will discuss opportunities associated translating inhibition into practice, including ongoing trials future directions HIF-based treatments.

Language: Английский

Citations

26
Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition DOI Creative Commons
Antonino Glaviano,

Hannah Lau,

Lukas M. Carter

et al.

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 13, 2025

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, signaling molecules that interact promote growth therapeutic resistance. Elucidating the intricate interactions between cells TME crucial in understanding progression challenges. A critical process induced by epithelial-mesenchymal transition (EMT), wherein epithelial acquire mesenchymal traits, which enhance their motility invasiveness progression. By targeting various components TME, novel investigational strategies aim disrupt TME's contribution EMT, thereby improving efficacy, addressing resistance, offering a nuanced approach therapy. This review scrutinizes key players emphasizing avenues therapeutically components. Moreover, article discusses implications for resistance mechanisms highlights current toward modulation along with potential caveats.

Language: Английский

Citations

26
Targeting of TAMs: can we be more clever than cancer cells? DOI Creative Commons
Julia Kzhyshkowska, Jiaxin Shen, Irina Larionova

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(12), P. 1376 - 1409

Published: Nov. 8, 2024

АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes death, reduced quality life disability worldwide. Principal progress in development new anticancer therapies, improving efficiency immunotherapeutic tools, personification conventional therapies needs to consider cancer-specific patient-specific programming innate immunity. Intratumoral TAMs their precursors, resident macrophages monocytes, are principal regulators tumor progression therapy resistance. Our review summarizes accumulated evidence for subpopulations number biomarkers, indicating predictive value clinical parameters carcinogenesis resistance, with a focus on solid cancers non-infectious etiology. We present state-of-the-art knowledge about tumor-supporting functions at all stages highlight recently identified by single-cell spatial analytical methods, that discriminate between tumor-promoting tumor-inhibiting TAMs, where both subtypes express combination prototype M1 M2 genes. focuses novel mechanisms involved crosstalk among epigenetic, signaling, transcriptional metabolic pathways TAMs. Particular attention has been given link cell metabolism epigenetic histone lactylation, which can be responsible unlimited protumoral Finally, we explain how interfere currently used therapeutics summarize most advanced data from trials, divide into four categories: inhibition TAM survival differentiation, monocyte/TAM recruitment tumors, functional reprogramming genetic enhancement macrophages.

Language: Английский

Citations

24
A feedback loop driven by H3K9 lactylation and HDAC2 in endothelial cells regulates VEGF-induced angiogenesis DOI Creative Commons
Wei Fan, Shuhao Zeng, Xiaotang Wang

et al.

Genome biology, Journal Year: 2024, Volume and Issue: 25(1)

Published: June 25, 2024

Vascular endothelial growth factor (VEGF) is one of the most powerful proangiogenic factors and plays an important role in multiple diseases. Increased glycolytic rates lactate accumulation are associated with pathological angiogenesis.

Language: Английский

Citations

23