Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition

Journal of Hematology & Oncology, Год журнала: 2025, Номер 18(1)

Опубликована: Янв. 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.

Язык: Английский

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Advances in Cell and Immune Therapies for Melanoma

Biomedicines, Год журнала: 2025, Номер 13(1), С. 98 - 98

Опубликована: Янв. 3, 2025

The incidence rate of cutaneous melanoma is on the rise worldwide, due to increased exposure UV radiation, aging populations, and teratogen agents. However, diagnosis more precise, number new cases related improved tools. Despite better early therapies, has remained a significant public health challenge because its aggressive behavior high potential for metastasis. In 2020, constituted approximately 1.3% all cancer deaths that occurred within European Union, thereby highlighting necessity effective prevention, timely diagnosis, sustainable treatment measures, especially as growing occur among younger patients. Melanoma regarded one most inflamed cancers immune cell presence strong response immunotherapy, fueling need development immune-driven innovative treatments. Approved including checkpoint inhibitors (e.g., anti-PD-1 anti-CTLA-4), have notably survival rates in melanoma. limitations PD-1/PD-L1 CTLA-4 axes inhibitors, such low rates, resistance, toxicity, driven continued research advancements strategies. Current clinical trials are exploring various combinations with costimulatory receptor agonists, chemotherapy, targeted other immunotherapies, goal improving outcomes reducing side effects Emerging approaches, adoptive therapy tumor-infiltrating lymphocytes (TILs) oncolytic virotherapy, showing promise. While CAR-T been less successful compared blood cancers, ongoing addressing challenges like tumor microenvironment antigen specificity. This review provides an overview requirement advances these medications, mark step forward management, set bring fresh breath hope

Язык: Английский

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ReCARving the future: bridging CAR T-cell therapy gaps with synthetic biology, engineering, and economic insights

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Сен. 5, 2024

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy solid tumors, safety concerns related to toxicity, and logistical challenges manufacturing scalability. This review critically examines latest advancements aimed at overcoming these obstacles, highlighting innovations CAR engineering, novel targeting strategies, improvements delivery persistence within tumor microenvironment. We also discuss development allogeneic T cells as off-the-shelf therapies, strategies mitigate adverse effects, integration with other therapeutic modalities. comprehensive analysis underscores synergistic potential enhance safety, efficacy, accessibility providing a forward-looking perspective on their evolutionary trajectory cancer treatment.

Язык: Английский

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Targeting refractory diffuse large B cell lymphoma by CAR-WEE1 T-cells: In vitro evaluation

Annals of Hematology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Abstract Refractory Diffuse Large B-cell Lymphoma (DLBCL) presents a major therapeutic challenge due to its resistance standard treatments. Engineered T-cells, especially Chimeric Antigen Receptor (CAR) have shown promise in overcoming drug resistance. This study investigates the effectiveness of WEE1-engineered T-cells targeting and eliminating refractory DLBCL vitro. CAR were created by transducing 5th-generation construct designed recognize WEE1, surface antigen commonly found on cells. The cytotoxic effect engineered was tested against Rituximab-resistant cells (RR-NU-DUL-1). Apoptosis cell cycle evaluated using flow cytometry. Quantitative Real-time PCR (RT-PCR) used measure expression BCL2, CDK2. results showed significant increase target lysis, apoptosis, necrosis, reduction percentage G2M phase cycle, as well decrease gene level, indicating strong anti-tumor activity. These findings suggest that T-cell therapy holds great for treating DLBCL, offering potential path clinical application. vitro evaluation highlights targeted treatment strategy emphasizing their applicability ability overcome mechanisms this aggressive lymphoma subtype.

Язык: Английский

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From Biology to Clinical Practice: The Bone Marrow Microenvironment in Multiple Myeloma

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(2), С. 327 - 327

Опубликована: Янв. 8, 2025

Multiple Myeloma (MM) is a complex hematological malignancy characterized by the clonal proliferation of malignant plasma cells within bone marrow (BM) [...].

Язык: Английский

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Non-small cell lung cancer and the tumor microenvironment: making headway from targeted therapies to advanced immunotherapy

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 10, 2025

Over the past decades, significant progress has been made in understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting development novel strategies for early detection wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized treatment landscape NSCLC. Nowadays, remain gold standard many patients, but still they suffer from adverse effects, including unexpected toxicity intrinsic acquired resistance mutations, which lead to relapse. The adoption immune checkpoint (ICIs) 2015, offered exceptional survival benefits patients without targetable alterations. Despite this notable progress, challenges remain, as not all respond favorably ICIs, therapy can develop time. A crucial factor influencing clinical response immunotherapy is microenvironment (TME). TME pivotal orchestrating interactions between neoplastic cells system, growth outcomes. In review, we discuss how intricate relationship success survey current state intervention, a focus on forthcoming promising chimeric antigen receptor (CAR) T sets major obstacles CAR-T therapies, creating conditions that suppress response, inducing exhaustion. To enhance efficacy, specific efforts associated NSCLC, should definitely TME-related immunosuppression escape by combining blockades.

Язык: Английский

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Tri-specific tribodies targeting 5T4, CD3, and immune checkpoint drive stronger functional T-cell responses than combinations of antibody therapeutics

Cell Death Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 10, 2025

Abstract One of the most promising cancer immunotherapies is based on bi-specific T-cell engagers (BiTEs) that simultaneously bind with one arm to a tumor-associated antigen tumor cells and other CD3 complex T form TCR-MHC independent immune synapse. We previously generated four novel tri-specific tribodies made up Fab targeting 5T4, an oncofetal expressed several types tumors, scFv cells, additional specific for checkpoint (IC), such as PD-1, PD-L1 or LAG-3. To verify their advantages over combinations BiTEs (CD3/TAA) IC inhibitors, recently used overcome immunosuppressive environment, here we tested functional properties in comparison clinically validated mAbs same ICs, alone combination control devoid immunomodulatory scFvs, called 53 P. found activated human peripheral blood mononuclear more efficiently than (atezolizumab, pembrolizumab, relatlimab) either P, leading stronger cytotoxicity cytokines release. In particular, 53L10 tribody displayed much potent effects P all led complete regression vivo, showing higher efficacy atezolizumab. shed light molecular basis this potentiated anti-tumor activity by evidencing insertion anti-PD-L1 moiety not only binding but also blocked increased induced IFNγ secretion due activation. These results are important design antigens.

Язык: Английский

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Regulatory T-cells: The Face-off of the Immune Balance

Frontiers in Bioscience-Landmark, Год журнала: 2024, Номер 29(11)

Опубликована: Ноя. 8, 2024

Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring balanced response. Tregs primarily operate an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. have been studied extensively, from point of origin the thymus to fate periphery or organs. Signals received antigen-presenting cells (APCs) stimulate dampen inflammation. Almost all tumors are characterized pathological abundance suppression microenvironment. Conversely, lack thereof proves detrimental immunological disorders. Achieving expression relation other compartments is important establishing effective and adaptable tolerance towards cancer autoantigens. In context cancer, it essential decrease frequency overcome tumor suppression. A lower survival rate associated with presence excessive exhausted effector increased regulatory cells. However, when comes treating graft rejection autoimmune diseases, focus lies on transfer Tregs. Here, we explore complex mechanisms that use human disease balance

Язык: Английский

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Checkpoint therapy in cancer treatment: progress, challenges, and future directions

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(18)

Опубликована: Сен. 16, 2024

Язык: Английский

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Solid cancer-directed CAR T-cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1

Deleted Journal, Год журнала: 2024, Номер 32(4), С. 200891 - 200891

Опубликована: Окт. 5, 2024

Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within TME, cells along with employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector cells; this makes PD-L1 a reliable, universal target for We developed novel CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed simultaneously cells. antigen-specific antitumor effects MC9999 were observed consistently across four models: breast cancer, lung melanoma, glioblastoma multiforme (GBM). Notably, intravenous administration eradicated intracranially established LN229 GBM tumors, suggesting penetration blood-brain barrier. proof-of-concept data demonstrate cytolytic effect against cells, including microglia HMC3 M2 macrophages. Furthermore, elicited cytotoxicity primary tumor-associated macrophages within concept targeting both was further validated derived from cancer patients. These findings establish as foundation development effective therapies

Язык: Английский

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