Alzheimer’s disease is the most prevalent form of dementia and major Tauopathies characterized by memory loss and cognitive decline. Important pathological features include extracellular build-up of amyloid-β peptides which form senile plaques, and the intracellular accumulation of Tau protein in oligomeric and filamentous forms. This pathological form of Tau spreads via prion-like propagation and leads to protein aggregation. The spread of pathological Tau through extracellular spaces is a serious concern in disease progression. Microglial G-protein coupled receptors (GPCRs), such as the chemokine receptor CX3CR1 and purinergic receptor P2Y12R, mediate Tau internalization to limit this propagation. Dysregulated GPCR signalling in AD can result in an excessive inflammatory response or inadequate clearance of Tau aggregates, contributing to neurotoxicity and neuroinflammation. This review explores different GPCR-mediated pathways in microglial cells and their regulation in Tau clearance, shedding light on promising mechanistic pathways to reduce Tau-related toxicity and inflammation in Alzheimer’s disease.
{"title":"Mechanisms and routes of G-protein coupled receptor-mediated Tau degradation in Alzheimer’s disease","authors":"Vaishnavi Ananthanarayana , Hariharakrishnan Chidamabram , Periyasamy Govindaraj , K Vijayalakshmi , Subashchandrabose Chinnathambi","doi":"10.1016/j.cytogfr.2025.07.003","DOIUrl":"10.1016/j.cytogfr.2025.07.003","url":null,"abstract":"<div><div>Alzheimer’s disease is the most prevalent form of dementia and major Tauopathies characterized by memory loss and cognitive decline. Important pathological features include extracellular build-up of amyloid-β peptides which form senile plaques, and the intracellular accumulation of Tau protein in oligomeric and filamentous forms. This pathological form of Tau spreads <em>via</em> prion-like propagation and leads to protein aggregation. The spread of pathological Tau through extracellular spaces is a serious concern in disease progression. Microglial G-protein coupled receptors (GPCRs), such as the chemokine receptor CX3CR1 and purinergic receptor P2Y12R, mediate Tau internalization to limit this propagation. Dysregulated GPCR signalling in AD can result in an excessive inflammatory response or inadequate clearance of Tau aggregates, contributing to neurotoxicity and neuroinflammation. This review explores different GPCR-mediated pathways in microglial cells and their regulation in Tau clearance, shedding light on promising mechanistic pathways to reduce Tau-related toxicity and inflammation in Alzheimer’s disease.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"85 ","pages":"Pages 118-129"},"PeriodicalIF":11.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.cytogfr.2025.07.004
Jing Zhou , Yi Yang , Yaning Fang , Xinyu Du , Zheye Ying , Chuangzhou Rao
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is an important component of innate immunity, involved in regulating various pathological conditions such as cancer, autoimmune and inflammatory diseases, microbial and parasitic infections. It also regulates various cellular physiological processes, including cytokine production, autophagy, protein synthesis, metabolism, aging, and different types of cell death. Cell death is essential for maintaining homeostasis, promoting tissue repair, and regeneration. Emerging evidence underscores the dynamic interplay between cGAS-STING signaling and cell death, highlighting their relevance in disease pathogenesis and progression. Therefore, elucidating the specific role of the cGAS-STING signaling pathway and associated cell death mechanisms in vivo is critical for targeted disease interventions. This review systematically investigates the mechanistic interactions between the cGAS-STING signaling pathway and cell death modalities, such as autophagy, necroptosis, apoptosis, pyroptosis, ferroptosis, and cuproptosis. Understanding these interactions may provide new therapeutic strategies. We particularly highlight the pathological relevance of cGAS-STING signaling pathway and cell death in human diseases, with a focus on autoimmune disorders, cancer, inflammation, and the impact of organ damage. By clarifying the molecular mechanisms linking cGAS-STING signaling pathway to various cell death modalities and their contributions to disease, we aim to provide a theoretical framework for the rational design of novel therapies targeting this pathway.
{"title":"Targeting cGAS-STING signaling and cell death modes in cancer and autoimmune diseases","authors":"Jing Zhou , Yi Yang , Yaning Fang , Xinyu Du , Zheye Ying , Chuangzhou Rao","doi":"10.1016/j.cytogfr.2025.07.004","DOIUrl":"10.1016/j.cytogfr.2025.07.004","url":null,"abstract":"<div><div>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is an important component of innate immunity, involved in regulating various pathological conditions such as cancer, autoimmune and inflammatory diseases, microbial and parasitic infections. It also regulates various cellular physiological processes, including cytokine production, autophagy, protein synthesis, metabolism, aging, and different types of cell death. Cell death is essential for maintaining homeostasis, promoting tissue repair, and regeneration. Emerging evidence underscores the dynamic interplay between cGAS-STING signaling and cell death, highlighting their relevance in disease pathogenesis and progression. Therefore, elucidating the specific role of the cGAS-STING signaling pathway and associated cell death mechanisms <em>in vivo</em> is critical for targeted disease interventions. This review systematically investigates the mechanistic interactions between the cGAS-STING signaling pathway and cell death modalities, such as autophagy, necroptosis, apoptosis, pyroptosis, ferroptosis, and cuproptosis. Understanding these interactions may provide new therapeutic strategies. We particularly highlight the pathological relevance of cGAS-STING signaling pathway and cell death in human diseases, with a focus on autoimmune disorders, cancer, inflammation, and the impact of organ damage. By clarifying the molecular mechanisms linking cGAS-STING signaling pathway to various cell death modalities and their contributions to disease, we aim to provide a theoretical framework for the rational design of novel therapies targeting this pathway.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"85 ","pages":"Pages 56-80"},"PeriodicalIF":11.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-16DOI: 10.1016/j.cytogfr.2025.06.004
Zhou Chen , Defeng Guan , Yan Wang , Yunjiu Gou
Macrophages support the malignant transformation of pancreatic ductal adenocarcinoma cells by secreting cytokines and enzymes, which enhance tumor invasiveness and metastatic potential. In addition to promoting tumor growth, macrophages contribute to drug resistance, radioresistance, and immune evasion mechanisms by interacting with both cancer cells and other immune components. Their role in promoting angiogenesis further illustrates their importance in sustaining a tumor-supportive environment. These insights have led to growing interest in macrophage-targeted therapies. Approaches under investigation include reprogramming macrophages to adopt tumor-inhibiting functions, combining conventional chemotherapy or radiotherapy with macrophage-specific treatments to overcome resistance, using immunotherapies to modulate macrophage activity and enhance anti-tumor immune responses, and employing nanoparticle-based drug delivery systems for precise targeting. A deeper understanding of the specific mechanisms by which macrophages influence pancreatic ductal adenocarcinoma progression is essential. Such knowledge will pave the way for more effective treatments and offer new therapeutic options for patients with this aggressive disease.
{"title":"Targeting macrophage-directed pathological processes in pancreatic ductal adenocarcinoma: Mechanisms and targeted therapies","authors":"Zhou Chen , Defeng Guan , Yan Wang , Yunjiu Gou","doi":"10.1016/j.cytogfr.2025.06.004","DOIUrl":"10.1016/j.cytogfr.2025.06.004","url":null,"abstract":"<div><div><span>Macrophages support the malignant transformation of </span>pancreatic ductal adenocarcinoma<span><span><span><span><span> cells by secreting cytokines and enzymes, which enhance tumor invasiveness and </span>metastatic potential<span>. In addition to promoting tumor growth, macrophages contribute to drug resistance, radioresistance, and immune evasion mechanisms by interacting with both </span></span>cancer cells<span> and other immune components. Their role in promoting angiogenesis further illustrates their importance in sustaining a tumor-supportive environment. These insights have led to growing interest in macrophage-targeted therapies. Approaches under investigation include reprogramming macrophages to adopt tumor-inhibiting functions, combining conventional chemotherapy or radiotherapy with macrophage-specific treatments to overcome resistance, using </span></span>immunotherapies to modulate macrophage activity and enhance anti-tumor immune responses, and employing nanoparticle-based </span>drug delivery systems<span> for precise targeting. A deeper understanding of the specific mechanisms by which macrophages influence pancreatic ductal adenocarcinoma progression is essential. Such knowledge will pave the way for more effective treatments and offer new therapeutic options for patients with this aggressive disease.</span></span></div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"85 ","pages":"Pages 130-145"},"PeriodicalIF":11.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-16DOI: 10.1016/j.cytogfr.2025.06.003
Mukesh Kumar Manickasamy , Ravichandran Vishwa , Bandari BharathwajChetty , Mohammed S. Alqahtani , Mohamed Abbas , Ajaikumar B. Kunnumakkara
Oral cancer remains one of the deadliest diseases due to its aggressive nature, high metastatic potential, and limited therapeutic success. The tumor microenvironment (TME) serves as a central regulator in the metastasis of oral cancer by shaping tumor-stroma interactions, immune modulation, and metastatic dissemination. Among the key regulators of the TME, cytokines act as one of the molecular orchestrators, mediating inflammation, immune suppression, epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. This review explores the regulatory networks driven by cytokines from TME that govern tumor metastasis in oral cancer. Pro-tumorigenic cytokines such as IL-6, IL-8, TGF-β, TNF-α, etc., drive EMT, extracellular matrix (ECM) remodeling, and immune evasion, facilitating tumor invasion and metastatic colonization. Conversely, anti-tumor cytokines, including IFN-γ, IL-12, etc., play a role in immune activation but are often downregulated in the immunosuppressive TME. Additionally, the complex crosstalk between immune cells, tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) further amplifies cytokine-driven tumor metastasis. Understanding the “cytokine symphony” that governs oral cancer progression and metastasis is critical for developing targeted therapies. Here, we discuss the cytokine crosstalk in TME and its implication in metastasis and conclude with an emerging cytokine-targeting strategy, including anti-IL-6/STAT3 inhibitors, IL-8 blockade, and immune checkpoint inhibitors, as potential approaches to modulate the TME and suppress oral cancer metastasis. Future clinical studies are essential to validate cytokine-based interventions and pave the way for precision medicine in oral cancer management.
{"title":"Cytokine symphony: Deciphering the tumor microenvironment and metastatic axis in oral cancer","authors":"Mukesh Kumar Manickasamy , Ravichandran Vishwa , Bandari BharathwajChetty , Mohammed S. Alqahtani , Mohamed Abbas , Ajaikumar B. Kunnumakkara","doi":"10.1016/j.cytogfr.2025.06.003","DOIUrl":"10.1016/j.cytogfr.2025.06.003","url":null,"abstract":"<div><div>Oral cancer remains one of the deadliest diseases due to its aggressive nature, high metastatic potential, and limited therapeutic success. The tumor microenvironment (TME) serves as a central regulator in the metastasis of oral cancer by shaping tumor-stroma interactions, immune modulation, and metastatic dissemination. Among the key regulators of the TME, cytokines act as one of the molecular orchestrators, mediating inflammation, immune suppression, epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. This review explores the regulatory networks driven by cytokines from TME that govern tumor metastasis in oral cancer. Pro-tumorigenic cytokines such as IL-6, IL-8, TGF-β, TNF-α, etc., drive EMT, extracellular matrix (ECM) remodeling, and immune evasion, facilitating tumor invasion and metastatic colonization. Conversely, anti-tumor cytokines, including IFN-γ, IL-12, etc., play a role in immune activation but are often downregulated in the immunosuppressive TME. Additionally, the complex crosstalk between immune cells, tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) further amplifies cytokine-driven tumor metastasis. Understanding the “cytokine symphony” that governs oral cancer progression and metastasis is critical for developing targeted therapies. Here, we discuss the cytokine crosstalk in TME and its implication in metastasis and conclude with an emerging cytokine-targeting strategy, including anti-IL-6/STAT3 inhibitors, IL-8 blockade, and immune checkpoint inhibitors, as potential approaches to modulate the TME and suppress oral cancer metastasis. Future clinical studies are essential to validate cytokine-based interventions and pave the way for precision medicine in oral cancer management.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"85 ","pages":"Pages 1-10"},"PeriodicalIF":11.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-06DOI: 10.1016/j.cytogfr.2025.06.002
Yong Wu , Wen-Min Lu , Qian-Ru Cui , Jing Zhou , Guo-Dong Lu
The cGAS-STING pathway, a cytosolic DNA-sensing mechanism, plays a context-dependent pivotal role in tumor immunity and tumor microenvironment (TME) remodeling. Acute activation of this pathway promotes type I interferon (IFN-I) and pro-inflammatory responses, including dendritic cell (DC) maturation and cytotoxic T cell recruitment, whereas chronic stimulation paradoxically drives immunosuppression and tumor progression through mechanisms such as PD-L1 upregulation and regulatory T cell activation. Tumor metabolic reprogramming—encompassing hypoxia, glycolysis, Krebs cycle metabolites, amino acids, lipids, TME acidity and redox species —emerges as a critical modulator of cGAS-STING activity. For instance, hypoxia suppresses cGAS-STING via TET1-mediated induction of miR-25 and miR-93, while oxygen supplementation reactivates antitumor immunity. Glucose flux exerts dual regulatory effects: NSUN2-dependent TREX2 stabilization limits cytosolic DNA accumulation, whereas glycolysis ATP fuels STING-dependent DC activation. Beyond tumor cells, cGAS-STING signaling in cancer-associated fibroblasts promotes chemoresistance via DNA damage repair, and endothelial STING activation normalizes tumor vasculature to alleviate TME hypoxia and improve T cell infiltration. Current therapeutic strategies prioritize isoform-specific agonists (e.g. cyclic dinucleotides like ADU-S100; non-CDNs like diABZI) and precision delivery systems, such as nanoparticles and engineered bacteria, to address challenges like short half-life and systemic toxicity. Synergistic approaches—including ACLY inhibition to amplify mitochondrial DNA release or pH-responsive nanoparticles co-delivering STING/TLR4 agonists—enhance efficacy when combined with checkpoint inhibitors and radiotherapy. However, the pathway’s dual roles, particularly its tumor-promoting effects in advanced malignancies, necessitate context-dependent modulation. This review integrates preclinical insights and clinical trial data to outline strategies for harnessing cGAS-STING signaling in cancer immunotherapy while balancing its immunostimulatory and immunosuppressive outputs.
{"title":"Metabolic Regulation of cGAS-STING Signaling in the Tumor Microenvironment: Dual Immune Roles and Therapeutic Implications","authors":"Yong Wu , Wen-Min Lu , Qian-Ru Cui , Jing Zhou , Guo-Dong Lu","doi":"10.1016/j.cytogfr.2025.06.002","DOIUrl":"10.1016/j.cytogfr.2025.06.002","url":null,"abstract":"<div><div><span><span>The cGAS-STING pathway, a cytosolic DNA-sensing mechanism, plays a context-dependent pivotal role in tumor immunity<span> and tumor microenvironment (TME) remodeling. Acute activation of this pathway promotes </span></span>type I interferon<span><span> (IFN-I) and pro-inflammatory responses, including dendritic cell (DC) maturation and cytotoxic T cell recruitment, whereas chronic stimulation paradoxically drives immunosuppression and tumor progression through mechanisms such as PD-L1 upregulation and </span>regulatory T cell<span> activation. Tumor metabolic reprogramming—encompassing hypoxia, glycolysis, </span></span></span>Krebs cycle<span><span><span><span> metabolites, amino acids<span>, lipids, TME acidity and redox species —emerges as a critical modulator of cGAS-STING activity. For instance, hypoxia suppresses cGAS-STING via TET1-mediated induction of miR-25 and miR-93, while oxygen supplementation reactivates antitumor immunity. Glucose flux exerts dual regulatory effects: NSUN2-dependent TREX2 stabilization limits cytosolic DNA accumulation, whereas glycolysis ATP fuels STING-dependent DC activation. Beyond tumor cells, cGAS-STING signaling in cancer-associated fibroblasts promotes chemoresistance via </span></span>DNA damage repair, and endothelial STING activation normalizes </span>tumor vasculature<span> to alleviate TME hypoxia and improve T cell infiltration<span><span><span>. Current therapeutic strategies prioritize isoform-specific agonists (e.g. cyclic </span>dinucleotides like ADU-S100; non-CDNs like diABZI) and precision delivery systems, such as </span>nanoparticles and engineered bacteria, to address challenges like short half-life and systemic toxicity. Synergistic approaches—including </span></span></span>ACLY<span><span> inhibition to amplify mitochondrial DNA release or pH-responsive nanoparticles co-delivering STING/TLR4 agonists—enhance efficacy when combined with checkpoint inhibitors and radiotherapy. However, the pathway’s dual roles, particularly its tumor-promoting effects in advanced malignancies, necessitate context-dependent modulation. This review integrates preclinical insights and clinical trial data to outline strategies for harnessing cGAS-STING signaling in </span>cancer immunotherapy<span> while balancing its immunostimulatory and immunosuppressive outputs.</span></span></span></div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"85 ","pages":"Pages 43-55"},"PeriodicalIF":11.8,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.cytogfr.2025.01.002
Anushka Saran , Daisuke Nishizaki , Scott M. Lippman , Shumei Kato , Razelle Kurzrock
IL-17A, referred to as IL-17, is the founding member of a family of pro-inflammatory cytokines, including IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F, which act via receptors IL-17RA to IL-17RE, and elicit potent cellular responses that impact diverse diseases. IL-17’s interactions with various cytokines include forming a heterodimer with IL-17F and being stimulated by IL-23’s activation of Th17 cells, which can lead to inflammation and autoimmunity. IL-17 is implicated in infectious diseases and inflammatory disorders such as rheumatoid arthritis and psoriasis, promoting neutrophil recruitment and anti-bacterial immunity, but potentially exacerbating fungal and viral infections, revealing its dual role as protective and pathologic. IL-17 is also involved in various cancers, including breast, colon, cervical, prostate, and skin cancer, contributing to proliferation, immune invasion, and metastases, but also playing a protective role in certain instances. Four FDA-approved drugs—secukinumab (for ankylosing spondylitis, enthesitis-related arthritis, hidradenitis suppurativa, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), ixekizumab (for ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), brodalumab (for plaque psoriasis), and bimekizumab (for plaque psoriasis)—suppress the IL-17 pathway, with more in development, including netakimab, sonelokimab, izokibep, and CJM112. These agents and others are being studied across a spectrum of disorders. Understanding the complicated interplay between IL-17 and other immune mediators may yield new treatments for inflammatory/autoimmune conditions and malignancies.
{"title":"Interleukin-17: A pleiotropic cytokine implicated in inflammatory, infectious, and malignant disorders","authors":"Anushka Saran , Daisuke Nishizaki , Scott M. Lippman , Shumei Kato , Razelle Kurzrock","doi":"10.1016/j.cytogfr.2025.01.002","DOIUrl":"10.1016/j.cytogfr.2025.01.002","url":null,"abstract":"<div><div>IL-17A, referred to as IL-17, is the founding member of a family of pro-inflammatory cytokines, including IL-17B, IL-17C, IL-17D, IL-17E (or IL-25), and IL-17F, which act via receptors IL-17RA to IL-17RE, and elicit potent cellular responses that impact diverse diseases. IL-17’s interactions with various cytokines include forming a heterodimer with IL-17F and being stimulated by IL-23’s activation of Th17 cells, which can lead to inflammation and autoimmunity. IL-17 is implicated in infectious diseases and inflammatory disorders such as rheumatoid arthritis and psoriasis, promoting neutrophil recruitment and anti-bacterial immunity, but potentially exacerbating fungal and viral infections, revealing its dual role as protective and pathologic. IL-17 is also involved in various cancers, including breast, colon, cervical, prostate, and skin cancer, contributing to proliferation, immune invasion, and metastases, but also playing a protective role in certain instances. Four FDA-approved drugs—secukinumab (for ankylosing spondylitis, enthesitis-related arthritis, hidradenitis suppurativa, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), ixekizumab (for ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis, and psoriatic arthritis), brodalumab (for plaque psoriasis), and bimekizumab (for plaque psoriasis)—suppress the IL-17 pathway, with more in development, including netakimab, sonelokimab, izokibep, and CJM112. These agents and others are being studied across a spectrum of disorders. Understanding the complicated interplay between IL-17 and other immune mediators may yield new treatments for inflammatory/autoimmune conditions and malignancies.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"83 ","pages":"Pages 35-44"},"PeriodicalIF":9.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.cytogfr.2025.02.001
Zhixin Wei , Kiya Babkirk , Song Chen , Ming Pei
The epithelial-mesenchymal transition transcription factors (EMT-TFs)—ZEB, SNAI, and TWIST families—have been extensively studied in embryonic development and tumor metastasis, providing valuable insight into their roles in cell behavior and transformation. These EMT-TFs have garnered increasing attention in the context of mesenchymal tissue regeneration, potentially contributing an approach for cell therapy. Given that dysregulated EMT-TF expression can impair cell survival and lineage differentiation, controlled regulation of their expression could offer significant advantages for tissue regeneration. However, there is a lack of comprehensive reviews to summarize the influence of the EMT-TFs on mesenchymal tissue regeneration and potential molecular mechanisms. This review explores the regulatory roles of ZEB, SNAI, and TWIST in the regeneration of bone, adipose, cartilage, muscle, and other mesenchymal tissues, with a focus on the underlying molecular signaling mechanisms. Gaining a deeper understanding of how EMT-TFs regulate cell proliferation, apoptosis, migration, and differentiation may offer new insights into the management of mesenchymal tissue repair and open novel avenues for enhancing tissue regeneration.
{"title":"Epithelial-to-mesenchymal transition transcription factors: New strategies for mesenchymal tissue regeneration","authors":"Zhixin Wei , Kiya Babkirk , Song Chen , Ming Pei","doi":"10.1016/j.cytogfr.2025.02.001","DOIUrl":"10.1016/j.cytogfr.2025.02.001","url":null,"abstract":"<div><div>The epithelial-mesenchymal transition transcription factors (EMT-TFs)—ZEB, SNAI, and TWIST families—have been extensively studied in embryonic development and tumor metastasis, providing valuable insight into their roles in cell behavior and transformation. These EMT-TFs have garnered increasing attention in the context of mesenchymal tissue regeneration, potentially contributing an approach for cell therapy. Given that dysregulated EMT-TF expression can impair cell survival and lineage differentiation, controlled regulation of their expression could offer significant advantages for tissue regeneration. However, there is a lack of comprehensive reviews to summarize the influence of the EMT-TFs on mesenchymal tissue regeneration and potential molecular mechanisms. This review explores the regulatory roles of ZEB, SNAI, and TWIST in the regeneration of bone, adipose, cartilage, muscle, and other mesenchymal tissues, with a focus on the underlying molecular signaling mechanisms. Gaining a deeper understanding of how EMT-TFs regulate cell proliferation, apoptosis, migration, and differentiation may offer new insights into the management of mesenchymal tissue repair and open novel avenues for enhancing tissue regeneration.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"83 ","pages":"Pages 99-124"},"PeriodicalIF":9.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.cytogfr.2025.04.002
Anran Wu , Tingying Zhang , Hongkai Yu , Yuyue Cao , Rui Zhang , Ruonan Shao , Bofeng Liu , Liting Chen , Kailin Xu , Wei Chen , Jinyuan Ho , Xiaofeng Shi
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a revolutionary approach in the treatment of hematological malignancies, including acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. Despite its promise, the clinical efficacy is often hampered by transient efficacy and subsequent relapse, which curtail the long-term success of this treatment. Current research focuses on overcoming these obstacles by exploring multitarget strategies and optimizing CAR-T cell design. This review summarizes recent insights into the resistance mechanisms associated with CAR-T cell therapy, and delineates emerging strategies for optimized CAR construction, including targeting multiple antigens, improving CAR design, and enhancing T-cell persistence. The goal is to provide a comprehensive overview of the field’s current landscape to guide future research and the clinical application of CAR-T cell therapies.
{"title":"Mechanisms underlying resistance to CAR-T cell therapy and strategies for enhancement","authors":"Anran Wu , Tingying Zhang , Hongkai Yu , Yuyue Cao , Rui Zhang , Ruonan Shao , Bofeng Liu , Liting Chen , Kailin Xu , Wei Chen , Jinyuan Ho , Xiaofeng Shi","doi":"10.1016/j.cytogfr.2025.04.002","DOIUrl":"10.1016/j.cytogfr.2025.04.002","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T-cell therapy has emerged as a revolutionary approach in the treatment of hematological malignancies, including acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. Despite its promise, the clinical efficacy is often hampered by transient efficacy and subsequent relapse, which curtail the long-term success of this treatment. Current research focuses on overcoming these obstacles by exploring multitarget strategies and optimizing CAR-T cell design. This review summarizes recent insights into the resistance mechanisms associated with CAR-T cell therapy, and delineates emerging strategies for optimized CAR construction, including targeting multiple antigens, improving CAR design, and enhancing T-cell persistence. The goal is to provide a comprehensive overview of the field’s current landscape to guide future research and the clinical application of CAR-T cell therapies.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"83 ","pages":"Pages 66-76"},"PeriodicalIF":9.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.cytogfr.2025.03.001
Harapriya Baral, Ravinder K. Kaundal
Traumatic brain injury (TBI) is a major global health concern and a leading cause of morbidity and mortality. Neuroinflammation is a pivotal driver of both the acute and chronic phases of TBI, with pattern recognition receptors (PRRs) playing a central role in detecting damage-associated molecular patterns (DAMPs) and initiating immune responses. Key PRR subclasses, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and cGAS-like receptors (cGLRs), are abundantly expressed in central nervous system (CNS) cells and infiltrating immune cells, where they mediate immune activation, amplify neuroinflammatory cascades, and exacerbate secondary injury mechanisms. This review provides a comprehensive analysis of these PRR subclasses, detailing their distinct structural characteristics, expression patterns, and roles in post-TBI immune responses. We critically examine the molecular mechanisms underlying PRR-mediated signaling and explore their contributions to neuroinflammatory pathways and secondary injury processes. Additionally, preclinical and clinical evidence supporting the therapeutic potential of targeting PRRs to mitigate neuroinflammation and improve neurological outcomes is discussed. By integrating recent advancements, this review offers an in-depth understanding of the role of PRRs in TBI pathobiology and underscores the potential of PRR-targeted therapies in mitigating TBI-associated neurological deficits.
{"title":"Novel insights into neuroinflammatory mechanisms in traumatic brain injury: Focus on pattern recognition receptors as therapeutic targets","authors":"Harapriya Baral, Ravinder K. Kaundal","doi":"10.1016/j.cytogfr.2025.03.001","DOIUrl":"10.1016/j.cytogfr.2025.03.001","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a major global health concern and a leading cause of morbidity and mortality. Neuroinflammation is a pivotal driver of both the acute and chronic phases of TBI, with pattern recognition receptors (PRRs) playing a central role in detecting damage-associated molecular patterns (DAMPs) and initiating immune responses. Key PRR subclasses, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and cGAS-like receptors (cGLRs), are abundantly expressed in central nervous system (CNS) cells and infiltrating immune cells, where they mediate immune activation, amplify neuroinflammatory cascades, and exacerbate secondary injury mechanisms. This review provides a comprehensive analysis of these PRR subclasses, detailing their distinct structural characteristics, expression patterns, and roles in post-TBI immune responses. We critically examine the molecular mechanisms underlying PRR-mediated signaling and explore their contributions to neuroinflammatory pathways and secondary injury processes. Additionally, preclinical and clinical evidence supporting the therapeutic potential of targeting PRRs to mitigate neuroinflammation and improve neurological outcomes is discussed. By integrating recent advancements, this review offers an in-depth understanding of the role of PRRs in TBI pathobiology and underscores the potential of PRR-targeted therapies in mitigating TBI-associated neurological deficits.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"83 ","pages":"Pages 18-34"},"PeriodicalIF":9.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.cytogfr.2025.05.002
Liyile Chen, Ken Kadoya, Tsutomu Endo, Norimasa Iwasaki, M.Alaa Terkawi
Bone is a dynamic tissue that constantly undergoes remodeling processes throughout life to maintain its structure and integrity. During this process, physiological bone turnover, which is shaped by apoptosis, occurs in cells in the bone microenvironment. The clearance of these apoptotic cells (ACs) is executed by phagocytes through a process called efferocytosis, which simply means taking to the grave "burial." Efferocytosis is a multistage process involving the recognition, binding, internalization, and digestion of ACs, culminating in the resolution of inflammation. Critically, aberrations in efferocytosis lead to the accumulation of apoptotic corpses, impairing tissue homeostasis and contributing to various pathologies as well as bone-related diseases. Emerging evidence suggests that modulating/activating efferocytosis at any stage represents a promising therapeutic strategy for managing bone-related diseases, especially those associated with aging and inflammation. This review discusses the current understanding of the cellular and molecular mechanisms of efferocytosis, its roles within the bone microenvironment, and potential therapeutic interventions targeting efferocytosis in age-related bone diseases.
{"title":"Efferocytosis at the frontline of homeostasis: Shaping the bone microenvironment and therapeutic implications in related diseases","authors":"Liyile Chen, Ken Kadoya, Tsutomu Endo, Norimasa Iwasaki, M.Alaa Terkawi","doi":"10.1016/j.cytogfr.2025.05.002","DOIUrl":"10.1016/j.cytogfr.2025.05.002","url":null,"abstract":"<div><div>Bone is a dynamic tissue that constantly undergoes remodeling processes throughout life to maintain its structure and integrity. During this process, physiological bone turnover, which is shaped by apoptosis, occurs in cells in the bone microenvironment. The clearance of these apoptotic cells (ACs) is executed by phagocytes through a process called efferocytosis, which simply means taking to the grave \"burial.\" Efferocytosis is a multistage process involving the recognition, binding, internalization, and digestion of ACs, culminating in the resolution of inflammation. Critically, aberrations in efferocytosis lead to the accumulation of apoptotic corpses, impairing tissue homeostasis and contributing to various pathologies as well as bone-related diseases. Emerging evidence suggests that modulating/activating efferocytosis at any stage represents a promising therapeutic strategy for managing bone-related diseases, especially those associated with aging and inflammation. This review discusses the current understanding of the cellular and molecular mechanisms of efferocytosis, its roles within the bone microenvironment, and potential therapeutic interventions targeting efferocytosis in age-related bone diseases.</div></div>","PeriodicalId":11132,"journal":{"name":"Cytokine & Growth Factor Reviews","volume":"83 ","pages":"Pages 85-98"},"PeriodicalIF":9.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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