Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 2, 2023

Abstract Despite centuries since the discovery and study of cancer, cancer is still a lethal intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as pivotal component tumor microenvironment. The versatility sophisticated mechanisms CAFs in facilitating progression been elucidated extensively, including promoting angiogenesis metastasis, inducing drug resistance, reshaping extracellular matrix, developing an immunosuppressive Owing to their robust tumor-promoting function, are considered promising target for oncotherapy. However, highly heterogeneous group cells. Some subpopulations exert inhibitory role growth, which implies that CAF-targeting approaches must be more precise individualized. This review comprehensively summarize origin, phenotypical, functional heterogeneity CAFs. More importantly, we underscore advances strategies clinical trials CAF various cancers, also progressions immunotherapy.

Language: Английский

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Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Oct. 2, 2023

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between microenvironment (TME) is observed, with TME providing supportive niche for CSC survival self-renewal, while CSCs, turn, influence polarization persistence TME, promoting an immunosuppressive state. Consequently, these interactions hinder efficacy current therapies, necessitating exploration novel therapeutic approaches modulate target CSCs. this review, we highlight intricate strategies employed by evade surveillance develop resistance therapies. Furthermore, examine dynamic interplay shedding light on how interaction impacts progression. Moreover, provide overview advanced that specifically which hold promise future clinical translational studies treatment.

Language: Английский

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Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer ( Allo CAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem progenitor into CAR-NKT cells, but the use of three-dimensional culture xenogeneic feeders precluded its clinical application. Here describe clinically guided method to differentiate expand IL-15-enhanced high yield purity. We generated targeting seven cancers and, multiple myeloma model, demonstrated their antitumor efficacy, expansion persistence. The also selectively depleted immunosuppressive tumor microenviroment antagonized immune evasion via triple CAR, TCR NK receptors. They exhibited stable hypoimmunogenic phenotype associated epigenetic signaling regulation did not induce detectable graft versus host disease or cytokine release syndrome. These properties support potential translation.

Language: Английский

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Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies

Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 31(1)

Published: Jan. 12, 2024

Abstract Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated an intricately immunosuppression entrenched within microenvironment (TME). Principal mechanisms underpinning evasion from CBIs encompass loss antigens, downregulation presentation, activation checkpoint pathways, initiation anti-apoptotic cascades, and induction dysfunction exhaustion. In this review, we delve into intrinsic underlying capacity resist proffer prospective stratagems navigate around these challenges.

Language: Английский

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Programmable synthetic receptors: the next-generation of cell and gene therapies

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

Published: Jan. 3, 2024

Abstract Cell and gene therapies hold tremendous promise for treating a range of difficult-to-treat diseases. However, concerns over the safety efficacy require to be further addressed in order realize their full potential. Synthetic receptors, synthetic biology tool that can precisely control function therapeutic cells genetic modules, have been rapidly developed applied as powerful solution. Delicately designed engineered, they finetune activities, i.e., regulate production dosed, bioactive payloads by sensing processing user-defined signals or biomarkers. This review provides an overview diverse receptor systems being used reprogram wide applications biomedical research. With special focus on four at forefront, including chimeric antigen receptors (CARs) Notch (synNotch) we address generalized strategies design, construct improve receptors. Meanwhile, also highlight expanding landscape well current challenges clinical translation.

Language: Английский

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Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(6), P. 1849 - 1874

Published: April 6, 2024

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there a growing demand for off-the-shelf universal therapies. In this study, we have generated CAR-engineered NKT (

Language: Английский

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MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy

Cancer Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Despite the success of cancer immunotherapy in treating hematologic malignancies, their efficacy solid tumors remains limited due to immunosuppressive tumor microenvironment (TME), which is mainly formed by myeloid-derived suppressor cells (MDSCs). MDSCs not only exert potent effects that hinder immune checkpoint inhibitors (ICIs) and adaptive cellular therapies, but they also promote advancement through non-immunological pathways, including promoting angiogenesis, driving epithelial-mesenchymal transition (EMT), contributing establishment pre-metastatic environments. While targeting alone or combination with conventional therapies has shown success, emerging evidence suggests MDSC blockade other immunotherapies holds great promise overcoming both immunological barriers. In this review, we discussed dual roles MDSCs, a particular emphasis on underexplored checkpoints strategies. We rationale behind strategies, potential advantages MDSC-mediated immunosuppression, challenges associated development. Additionally, highlight future research directions aimed at optimizing enhance therapeutic effectiveness, particularly where are highly prevalent.

Language: Английский

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Generating allogeneic CAR-NKT cells for off-the-shelf cancer immunotherapy with genetically engineered HSP cells and feeder-free differentiation culture

Nature Protocols, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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New cell sources for CAR-based immunotherapy

Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: May 6, 2023

Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success some hematological malignancies preclinical clinical trials, resulting six FDA-approved CAR-T products currently available the market. Despite impressive outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of cells remain. While main focus been on improving exploring alternative cellular sources for CAR generation garnered growing interest. In current review, we comprehensively evaluated other rather than conventional generation.

Language: Английский

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Strategies for overcoming bottlenecks in allogeneic CAR-T cell therapy

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 24, 2023

Patient-derived autologous chimeric antigen receptor (CAR)-T cell therapy is a revolutionary breakthrough in immunotherapy and has made impressive progress both preclinical clinical studies. However, CAR-T cells still have notable drawbacks manufacture, such as long production time, variable potency possible manufacturing failures. Allogeneic significantly superior to these aspects. The use of allogeneic may provide simplified process allow the creation ‘off-the-shelf’ products, facilitating treatments various types tumors at less delivery time. Nevertheless, severe graft-versus-host disease (GvHD) or host-mediated allorejection occur setting, implying that addressing two critical issues urgent for application therapy. In this review, we summarize current approaches overcome GvHD host rejection, which empower with broader future.

Language: Английский

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