Macrophage plasticity: signaling pathways, tissue repair, and regeneration

MedComm, Journal Year: 2024, Volume and Issue: 5(8)

Published: Aug. 1, 2024

Abstract Macrophages are versatile immune cells with remarkable plasticity, enabling them to adapt diverse tissue microenvironments and perform various functions. Traditionally categorized into classically activated (M1) alternatively (M2) phenotypes, recent advances have revealed a spectrum of macrophage activation states that extend beyond this dichotomy. The complex interplay signaling pathways, transcriptional regulators, epigenetic modifications orchestrates polarization, allowing respond stimuli dynamically. Here, we provide comprehensive overview the cascades governing focusing on roles Toll‐like receptors, signal transducer activator transcription proteins, nuclear microRNAs. We also discuss emerging concepts metabolic reprogramming trained immunity, contributing their functional adaptability. Macrophage plasticity plays pivotal role in repair regeneration, macrophages coordinating inflammation, angiogenesis, matrix remodeling restore homeostasis. By harnessing potential novel therapeutic strategies targeting polarization could be developed for diseases, including chronic wounds, fibrotic disorders, inflammatory conditions. Ultimately, deeper understanding molecular mechanisms underpinning will pave way innovative regenerative medicine engineering approaches.

Language: Английский

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Human CSPG4-targeting CAR-macrophages inhibit melanoma growth

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Abstract Approximately half of melanoma patients relapse or fail to respond current standards care, highlighting the need for new treatment options. Engineering T-cells with chimeric antigen receptors (CARs) has revolutionized hematological malignancies but been clinically less effective in solid tumors. We therefore sought engineer alternative immune cell types inhibit progression. macrophages CARs emerged as a promising approach overcome some challenges faced by CAR-T cells; however, whether these engineered can effectively growth is unknown. To determine CAR-macrophages (CAR-Ms) specifically target and kill cells, we CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4), an expressed melanoma. CSPG4-targeting exhibited specific phagocytosis CSPG4-expressing cells. developed 3D approaches show that efficiently infiltrated spheroids. Furthermore, combining strategies inhibiting CD47/SIRPα “don’t eat me” signaling synergistically enhanced CAR-M-mediated robustly inhibited spheroid 3D. Importantly, tumor mouse models. These results suggest engineering against antigens immunotherapy treating

Language: Английский

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CAR Macrophages: a promising novel immunotherapy for solid tumors and beyond

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Aug. 23, 2024

Abstract With the advent of adoptive cellular therapy, chimeric antigen receptor (CAR)-T cell therapy has gained widespread application in cancer treatment and demonstrated significant efficacy against certain hematologic malignancies. However, due to limitations CAR-T treating solid tumors, other immune cells are being modified with CAR address this issue. Macrophages have emerged as a promising option, owing their extensive functions, which include presentation, powerful tumor phagocytosis, particularly active trafficking microenvironment. Leveraging unique advantages, CAR-macrophages (CAR-M) expected enhance effectiveness treatments novel form immunotherapy, potentially overcoming major challenges associated CAR-T/NK therapy. This review outlines primary mechanism underlying CAR-M recent progressions while also discussing further applications.

Language: Английский

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The next frontier in immunotherapy: potential and challenges of CAR-macrophages

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 5, 2024

Abstract Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers promising approach to target and eradicate tumor cells by utilizing macrophages’ phagocytic antigen-presenting abilities. However, challenges such as the complex microenvironment (TME), variability expression, immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of action, optimal construct designs, interactions within TME. It also delves into ex vivo manufacturing CAR-MΦ, discussing autologous allogeneic sources importance stringent quality control. The potential synergies integrating with existing cancer like checkpoint inhibitors conventional chemotherapeutics are examined highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways scrutinized alongside established protocols cells, identifying unique considerations essential clinical trials market approval. Proposed safety monitoring frameworks aim manage adverse events, cytokine release syndrome, crucial patient safety. Consolidating current research insights, this seeks refine therapeutic applications, overcome barriers, suggest future directions transition from experimental platforms standard care options.

Language: Английский

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Exploring CAR-macrophages in non-tumor diseases: Therapeutic potential beyond cancer

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

After significant advancements in tumor treatment, personalized cell therapy based on chimeric antigen receptors (CAR) holds promise for transforming the management of various diseases. CAR-T therapy, first approved CAR product, has demonstrated therapeutic potential treating infectious diseases, autoimmune disorders, and fibrosis. CAR-macrophages (CAR-Ms) are emerging as a promising approach immune particularly solid highlighting feasibility using macrophages to eliminate pathogens abnormal cells.

Language: Английский

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The efferocytosis dilemma: how neutrophil extracellular traps and PI3K/Rac1 complicate diabetic wound healing

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 21, 2025

Abstract Aims/hypothesis The resolution of apoptotic cells (ACs) is crucial for wound healing and tissue remodeling often impaired by persistent inflammation. This study aimed to elucidate the impact neutrophil extracellular traps (NETs) on diabetic targeting phosphoinositide 3-kinase/Ras-related C3 botulinum toxin substrate 1 (PI3K/Rac1) signaling pathway, which pivotal macrophage efferocytosis. Methods A streptozotocin-induced mouse model was used assess NETs efferocytosis in vivo. effects were evaluated using specific inhibitors agonists PI3K/Rac1 pathway. In vitro, macrophages from wounds or cell lines (Raw264.7) treated with a panel pharmacological agents pathway evaluate Results found inhibit efferocytosis, resulting delayed clearance ACs that accumulate within wounds. Inhibition NET formation mice rescued accompanied reactivation PI3K Rac1 macrophages. Moreover, restored NETs-induced impairment leading rapid healing. Raw264.7 exhibited elevated activation levels when co-cultured vitro. Nevertheless, this inhibited cultured NETs-conditioned medium, attenuated Conclusions/interpretation Targeting emerges as potential therapeutic strategy enhance promoting

Language: Английский

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Mitochondrial Dynamics and Metabolism in Macrophages for Cardiovascular Disease: a review

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156620 - 156620

Published: March 7, 2025

Language: Английский

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Are monocytes a preferable option to develop myeloid cell-based therapies for solid tumors?

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: March 15, 2025

Abstract In the last two decades, novel and promising cell-based therapies have populated treatment landscape for haematological tumors. However, commonly exploited T NK show limited applicability to solid This is mainly given by impaired tumor trafficking capability effector activity of these cells within a highly immunosuppressive microenvironment. Myeloid spontaneously home tumors can thus be reprogrammed and/or engineered directly attack or locally selectively deliver therapeutically relevant payloads that may improve efficacy immunotherapy against difficult-to-access context myeloid therapies, adoptive transfer monocytes has often been overshadowed infusion differentiated macrophages hematopoietic stem cell transplantation despite their therapeutic potential. Here, we summarize recent improvements benefits using tumors, current clinical applications challenges use as well some possible strategies overcome them.

Language: Английский

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The Atherosclerotic Plaque Microenvironment as a Therapeutic Target

Current Atherosclerosis Reports, Journal Year: 2025, Volume and Issue: 27(1)

Published: April 2, 2025

Atherosclerosis is traditionally viewed as a disease triggered by lipid accumulation, but growing evidence underscores the crucial role of plaque microenvironment in progression. This review explores recent advances understanding how cellular and extracellular components milieu drive atherosclerosis, with focus on leveraging these microenvironmental factors for therapeutic intervention. highlights cell-cell crosstalk matrix remodeling, offering insights into innovative strategies atherosclerotic cardiovascular disease. While atherosclerosis begins subendothelial retention apolipoprotein B (ApoB)-containing lipoproteins​, its progression increasingly recognized consequence complex dynamics within microenvironment. Soluble proteins shape mechanical properties biochemical landscape, directly influencing cell behavior inflammatory signaling. For instance, deposition transitional proteins, such fibronectin, regions disturbed flow primes endothelial cells inflammation​. Likewise, impaired clearance dead chronic remodeling contribute to lesion expansion instability, further exacerbating severity. Targeting presents promising avenue stabilizing lesions. Approaches that enhance beneficial interactions, boosting macrophage efferocytosis resolve inflammation while mitigating proatherogenic signals like integrin-mediated activation, may promote fibrous cap formation reduce vulnerability. Harnessing mechanisms lead novel approaches aimed at modifying combat

Language: Английский

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Silencing of SIRPα enhances the antitumor efficacy of CAR-M in solid tumors

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(11), P. 1335 - 1349

Published: Oct. 8, 2024

The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47-SIRPα interaction with CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing humanized single-chain variable fragment FcγRIIa and integrating short hairpin RNA silence SIRPα, thereby disrupting signaling pathway. These modified CAR-shSIRPα-M exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, ability eliminate patient-derived organoids. In vivo, CAR-M inhibited growth prolonged survival in tumor-bearing mice. Notably, enhanced T-cell infiltration into tumors, enhancing antitumor response both immune system mouse model immunocompetent Mechanistically, SIRPα inhibition activated inflammatory pathways cGAS-STING cascade leading increased production proinflammatory cytokines, reactive oxygen species, nitric oxide, effects. findings underscore novel strategy increase efficacy immunotherapy, particularly against solid tumors.

Language: Английский

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