Regulatory mechanisms of PD-1/PD-L1 in cancers

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Май 18, 2024

Abstract Immune evasion contributes to cancer growth and progression. Cancer cells have the ability activate different immune checkpoint pathways that harbor immunosuppressive functions. The programmed death protein 1 (PD-1) cell ligands (PD-Ls) are considered be major molecules. interaction of PD-1 PD-L1 negatively regulates adaptive response mainly by inhibiting activity effector T while enhancing function regulatory (Tregs), largely contributing maintenance homeostasis prevents dysregulated immunity harmful responses. However, exploit PD-1/PD-L1 axis cause escape in development Blockade neutralizing antibodies restores enhances anti-tumor immunity, achieving remarkable success therapy. Therefore, mechanisms cancers attracted an increasing attention. This article aims provide a comprehensive review roles signaling human autoimmune diseases cancers. We summarize all aspects underlying expression cancers, including genetic, epigenetic, post-transcriptional post-translational mechanisms. In addition, we further progress clinical research on antitumor effects targeting alone combination with other therapeutic approaches, providing new strategies for finding tumor markers developing combined approaches.

Язык: Английский

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Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Сен. 22, 2023

Cancer is a borderless global health challenge that continues to threaten human health. Studies have found oxidative stress (OS) often associated with the etiology of many diseases, especially aging process and cancer. Involved in OS reaction as key transcription factor, Nrf2 pivotal regulator cellular redox state detoxification. can prevent damage by regulating gene expression antioxidant response elements (ARE) promote process. generated an imbalance promotes accumulation mutations genome instability, thus establishment development different cancers. activation regulates plethora processes inducing proliferation, differentiation death, strongly OS-mediated What’s more, also involved anti-inflammatory effects metabolic disorders, neurodegenerative multidrug resistance. highly expressed multiple body parts digestive system, respiratory reproductive system nervous system. In oncology research, has emerged promising therapeutic target. Therefore, certain natural compounds drugs exert anti-cancer through signaling pathway, blocking pathway reduce some types tumor recurrence rates increase sensitivity chemotherapy. However, Nrf2’s dual role controversial impact cancer are inevitable consideration factors when treating this review, we summarized current biological characteristics its mechanism cells, discussed Keap1/Nrf2/ARE downstream genes, elaborated related pathways such AMPK/mTOR NF-κB. Besides, main target strategies using inhibitors or activators, well possible positive negative were reviewed. It be concluded serves important factor formation development, provides basis for targeted therapy

Язык: Английский

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Targeted protein degradation: advances in drug discovery and clinical practice

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Язык: Английский

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A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 6, 2025

The lysosome-targeting chimera (LYTAC) strategy provided a very powerful tool for the degradation of membrane proteins. However, synthesis LYTACs, antibody-small molecule conjugates, is challenging. ability antibody-based LYTACs to penetrate solid tumor limited as well, especially cross blood-brain barrier (BBB). Here, we propose covalent chimeric peptide-based targeted platform (Pep-TACs) by introducing long flexible aryl sulfonyl fluoride group, which allows proximity-enabled cross-linking upon binding with protein interest. Pep-TACs facilitates target proteins through mechanism recycling transferrin receptor (TFRC)-mediated lysosomal endocytosis. Biological experiments demonstrate that can significantly degrade expression PD-L1 on cells, dendritic cells and macrophages, under acidic conditions, markedly enhance function T phagocytosis macrophages. Furthermore, both in anti-PD-1-responsive -resistant models, exert significant anti-tumor immune response. It noteworthy BBB prolong survival mice situ brain tumor. As proof-of-concept, this study introduces modular TFRC-based peptide protein, immunotherapy tumors. LYTAC strategies often face challenges penetration synthesis. authors introduce Pep-TACs, effectively degrades PD-L1. This approach suppresses growth, particularly

Язык: Английский

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AXL signaling in cancer: from molecular insights to targeted therapies

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 9, 2025

Abstract AXL, a member of the TAM receptor family, has emerged as potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays significant role various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial–mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, inflammatory responses. Beyond oncology, AXL also facilitates viral infections, SARS-CoV-2 Zika highlighting its importance both virology. In preclinical models, small-molecule kinase inhibitors targeting have shown promising anti-tumorigenic potential. This review primarily focuses on induction, regulation biological functions mediating these pathways. We discuss range strategies, recently developed tyrosine (TKIs), monoclonal antibodies, antibody–drug conjugates (ADCs), anti-AXL-CAR, combination therapies. These interventions are being examined clinical studies, offering improved drug sensitivity efficacy. further mechanisms particularly crosstalk between other critical kinases (RTKs) such c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, FLT3. Finally, we highlight key research areas that require exploration to enhance AXL-mediated approaches outcomes.

Язык: Английский

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Nanoparticles in Medicine: Current Status in Cancer Treatment

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(16), С. 12827 - 12827

Опубликована: Авг. 15, 2023

Cancer is still a leading cause of deaths worldwide, especially due to those cases diagnosed at late stages with metastases that are considered untreatable and managed in such way lengthy chronic state achieved. Nanotechnology has been acknowledged as one possible solution improve existing cancer treatments, but also an innovative approach developing new therapeutic solutions will lower systemic toxicity increase targeted action on tumors metastatic tumor cells. In particular, the nanoparticles studied context treatment include organic inorganic particles whose role may often be expanded into diagnostic applications. Some best metallic gold silver nanoparticles, quantum dots, polymeric carbon nanotubes graphene, diverse mechanisms as, for example, increased induction reactive oxygen species, cellular uptake functionalization properties improved delivery. Recently, novel cell targeting nanobubbles, which have already demonstrated localization anticancer molecules tissues. this review, we accordingly present discuss state-of-the-art nano-formulations limitations their application clinical setting.

Язык: Английский

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PROTACs: Novel tools for improving immunotherapy in cancer

Cancer Letters, Год журнала: 2023, Номер 560, С. 216128 - 216128

Опубликована: Март 16, 2023

Язык: Английский

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The advance of the third‑generation EGFR‑TKI in the treatment of non‑small cell lung cancer (Review)

Oncology Reports, Год журнала: 2023, Номер 51(1)

Опубликована: Дек. 5, 2023

Lung cancer is currently the second most common type of with incidence rate and first mortality worldwide. Non‑small cell lung (NSCLC) accounts for ~85% total number cases cancers. Concerning treatment NSCLC, targeted therapy has become a research hotspot in recent years because its favorable efficacy, high selectivity minimal adverse reactions. Among drugs used therapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are categorized into four generations. The use second‑generation leads to drug resistance within 8‑14 months. This primarily caused by T790M mutation, which observed mechanism. A third‑generation been developed address this issue fourth‑generation expected overcome multiple mechanisms, including resistance. However, not launched yet. At present, have globally, three being China several at clinical trial stages. present article provides review development process, mechanism action trials EGFR‑TKIs, aiming provide some reference suggestions NSCLC scientific on drugs.

Язык: Английский

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A Potential “Anti-Warburg Effect” in Circulating Tumor Cell-mediated Metastatic Progression?

Aging and Disease, Год журнала: 2024, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2024

Metabolic reprogramming is a defining hallmark of cancer metastasis, warranting thorough exploration. The tumor-promoting function the "Warburg Effect", marked by escalated glycolysis and restrained mitochondrial activity, widely acknowledged. Yet, functional significance mitochondria-mediated oxidative phosphorylation (OXPHOS) during metastasis remains controversial. Circulating tumor cells (CTCs) are considered metastatic precursors that detach from primary or secondary sites harbor potential to seed distant metastases through hematogenous dissemination. A comprehensive metabolic characterization CTCs faces formidable obstacles, including isolation these rare billions blood cells, coupled with complexities ex vivo-culturing CTC lines establishment CTC-derived xenograft models (CDX). This review summarized role Effect" in both tumorigenesis CTC-mediated metastasis. Intriguingly, bioinformatic analysis single-CTC transcriptomic studies unveils OXPHOS dominance over Glycolysis signature genes across several important types. From observations, we postulate "Anti-Warburg (AWE) CTCs—a shift bridging tumors metastases. observed AWE could be clinically as they significantly correlated therapeutic response melanoma prostate patients. Thus, unraveling dynamic regulations within populations might reveal an additional layer regulatory providing avenue for innovative anti-metastasis therapies.

Язык: Английский

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Overcoming tyrosine kinase inhibitor resistance in lung cancer brain metastasis with CTLA4 blockade

Cancer Cell, Год журнала: 2024, Номер 42(11), С. 1882 - 1897.e7

Опубликована: Окт. 17, 2024

Язык: Английский

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