Biomarker Research最新文献

{"title":"Heat shock proteins (HSPs) in non-alcoholic fatty liver disease (NAFLD): from molecular mechanisms to therapeutic avenues.","authors":"Zhenwang Nie, Congshu Xiao, Yingzi Wang, Rongkuan Li, Fangcheng Zhao","doi":"10.1186/s40364-024-00664-z","DOIUrl":"https://doi.org/10.1186/s40364-024-00664-z","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver conditions characterized by fat accumulation without excessive alcohol consumption, represents a significant global health burden. The intricate molecular landscape underlying NAFLD pathogenesis involves lipid handling, inflammation, oxidative stress, and mitochondrial dysfunction, with endoplasmic reticulum (ER) stress emerging as a key contributor. ER stress triggers the unfolded protein response (UPR), impacting hepatic steatosis in NAFLD and contributing to inflammation, fibrosis, and progression to NASH and eventually hepatocellular carcinoma (HCC). Heat shock proteins (HSPs), including small HSPs such as HSP20 and HSP27, HSP60, HSP70, GRP78, and HSP90, are integral to cellular stress responses. They aid in protein folding, prevent aggregation, and facilitate degradation, thus mitigating cellular damage under stress conditions. In NAFLD, aberrant HSP expression and function contribute to disease pathogenesis. Understanding the specific roles of HSP subtypes in NAFLD offers insights into potential therapeutic interventions. This review discusses the involvement of HSPs in NAFLD pathophysiology and highlights their therapeutic potential. By elucidating the molecular mechanisms underlying HSP-mediated protection in NAFLD, this article aims to pave the way for the development of targeted therapies for this prevalent liver disorder.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"120"},"PeriodicalIF":9.5,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142480588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Redefining prostate cancer risk stratification: a pioneering strategy to estimate outcome based on Ki67 immunoscoring.","authors":"Ângela Albuquerque-Castro, Catarina Macedo-Silva, Rúben Oliveira-Sousa, Vera Constâncio, João Lobo, Isa Carneiro, Rui Henrique, Carmen Jerónimo","doi":"10.1186/s40364-024-00670-1","DOIUrl":"https://doi.org/10.1186/s40364-024-00670-1","url":null,"abstract":"","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"121"},"PeriodicalIF":9.5,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142480586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into the role of immunomodulatory extracellular vesicles in the pathogenesis of liver fibrosis.","authors":"Jiaxuan Li, Yue Yuan, Qinggang Fu, Min Chen, Huifang Liang, Xiaoping Chen, Xin Long, Bixiang Zhang, Jianping Zhao, Qian Chen","doi":"10.1186/s40364-024-00669-8","DOIUrl":"https://doi.org/10.1186/s40364-024-00669-8","url":null,"abstract":"<p><p>Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"119"},"PeriodicalIF":9.5,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142480589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin-permeable gold nanoparticles with modifications azelamide monoethanolamine ameliorate inflammatory skin diseases.","authors":"He Zhao, Han Zhao, Yan Tang, Mengfan Li, Yisheng Cai, Xin Xiao, Fanping He, Hongwen Huang, Yiya Zhang, Ji Li","doi":"10.1186/s40364-024-00663-0","DOIUrl":"10.1186/s40364-024-00663-0","url":null,"abstract":"<p><strong>Background: </strong>Traditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases.</p><p><strong>Methods: </strong>Here, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs.</p><p><strong>Results: </strong>We found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9.</p><p><strong>Conclusion: </strong>Au-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"118"},"PeriodicalIF":9.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis reveals alternations between the aged and young mice prostates.","authors":"Yang Li, Yuhong Ding, Yaxin Hou, Lilong Liu, Zhenghao Liu, Zhipeng Yao, Pengjie Shi, Jinxu Li, Ke Chen, Junyi Hu","doi":"10.1186/s40364-024-00666-x","DOIUrl":"10.1186/s40364-024-00666-x","url":null,"abstract":"<p><strong>Background: </strong>Aging of the male prostate is an inevitable process in which the prostate undergoes hyperplasia, and this growth may lead to compression of the urethra, resulting in voiding dysfunction and associated symptoms, and an increased risk of prostate cancer. Despite the significance of prostate aging, the molecular mechanisms involved are still not fully understood.</p><p><strong>Methods: </strong>Prostate split by lobes from young (2 months) and aged (24 months) mice were collected for single-cell RNA sequencing (scRNA-seq) analysis. Tissues from both anterior prostate (AP) and ventral/dorsal/lateral prostate (VDLP) were included in the study. Data analysis included unsupervised clustering using the uniform manifold approximation and projection (UMAP) algorithm to identify distinct cell types based on marker gene expression. Differential gene expression analysis was performed to identify age-related changes in gene expression across different cell types. Functional enrichment analysis was conducted to elucidate biological pathways associated with differentially expressed genes. Additionally, cellular interactions and developmental trajectories were analyzed to characterize cellular dynamics during prostate aging.</p><p><strong>Results: </strong>The single-cell transcriptome analysis of the mouse prostate during aging revealed heterogeneity across various cell types and their changes during the aging process. We found a significant increase in the proportion of mesenchymal and immune cells in aged mice. Our study unveiled alterations in genes and pathways associated with cellular senescence, oxidative stress, and regeneration in epithelial cells. Furthermore, we observed that basal cells may undergo epithelial-mesenchymal transition (EMT) to become mesenchymal cells, particularly prominent in aged mice. Additionally, immune cells, notably macrophages and T cells, exhibited a heightened inflammatory response in aged mice.</p><p><strong>Conclusion: </strong>In summary, our study provides a comparative analysis of the single-cell transcriptome of the aged and young mice prostates, elucidating cellular and molecular changes between the aged and young mice prostates.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"117"},"PeriodicalIF":9.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble PD-L1 as a novel biomarker predicts poor outcomes and disease progression in de novo myelodysplastic syndromes.","authors":"Xingcheng Yang, Lijun Jiang, Xiaoying Zhang, Juan Peng, Hu Qian, Lifang Huang, Shaolong He, Zhiqiong Wang, Liting Chen, Yicheng Zhang, Ling Ma, Yuan Chen, Jia Wei","doi":"10.1186/s40364-024-00665-y","DOIUrl":"10.1186/s40364-024-00665-y","url":null,"abstract":"<p><p>The role of the compromised immune microenvironment, including immune checkpoints, in myelodysplastic syndromes (MDS) has been identified as critical This study aimed to investigate the expression patterns of immune checkpoints, particularly soluble PD-1/PD-L1 (sPD-1/sPD-L1) as well as PD-1 on effector T cell subsets, and assess their prognostic value and potential regulatory roles in MDS. 161 MDS patients were enrolled, including 129 patients were primarily diagnosed with de novo MDS, together with 59 MDS patients who underwent hypomethylating agents (HMAs) therapy. Plasma sPD-L1 level was elevated in newly diagnosed MDS patients, which was also found to be associated with MDS disease progression that further increase in higher IPSS-R score group. Patients with increased sPD-L1 expression at diagnosis exhibited notably poorer overall survival, and multivariate Cox analysis indicated that elevated sPD-L1 was an independent risk factor. Furthermore, the levels of multiple cytokines and membrane-bound PD-1 on T cells were found to correlate with sPD-1/sPD-L1 levels in plasma. Importantly, we also found sPD-L1 levels significantly increased in MDS patients who showed progression of disease following HMAs therapy. In conclusion, we found elevated plasma sPD-L1 levels in MDS patients are associated with disease progression and poorer overall survival. This study showed that sPD-L1 is a potential biomarker for prognosis and a target for immunotherapy in MDS.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"115"},"PeriodicalIF":9.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell spatial profiling of FFPE splenic tissue from a humanized mouse model of HIV infection.","authors":"Guoxin Wu, Samuel H Keller, Luca Sardo, Brian Magliaro, Paul Zuck, Carl J Balibar, Claire Williams, Liuliu Pan, Mark Gregory, Kathy Ton, Jill Maxwell, Carol Cheney, Tom Rush, Bonnie J Howell","doi":"10.1186/s40364-024-00658-x","DOIUrl":"10.1186/s40364-024-00658-x","url":null,"abstract":"<p><strong>Background: </strong>Latency remains a major obstacle to finding a cure for HIV despite the availability of antiretroviral therapy. Due to virus dormancy, limited biomarkers are available to identify latent HIV-infected cells. Profiling of individual HIV-infected cells is needed to explore potential latency biomarkers and to study the mechanisms of persistence that maintain the HIV reservoir.</p><p><strong>Methods: </strong>Single cell spatial transcriptomic characterization using the CosMx Spatial Molecular Imager platform was conducted to analyze HIV-infected cells in formalin-fixed paraffin-embedded sections of splenic tissue surgically obtained from an HIV-infected humanized mouse model. Regulation of over a thousand human genes was quantified in both viremic and aviremic specimens. In addition, in situ hybridization and immunohistochemistry were performed in parallel to identify HIV viral RNA- and p24-containing cells, respectively. Finally, initial findings from CosMx gene profiling were confirmed by isolating RNA from CD4 + T cells obtained from a person living with HIV on antiretroviral therapy following either PMA/Ionomycin or DMSO treatment. RNA was quantified using qPCR for a panel of targeted human host genes.</p><p><strong>Results: </strong>Supervised cell typing revealed that most of the HIV-infected cells in the mouse spleen sections were differentiated CD4 + T cells. A significantly higher number of infected cells, 2781 (1.61%) in comparison to 112 (0.06%), and total HIV transcripts per infected cell were observed in viremic samples compared to aviremic samples, respectively, which was consistent with the data obtained from ISH and IHC. Notably, the expression of 55 genes was different in infected cells within tissue from aviremic animals compared to viremic. In particular, both spleen tyrosine kinase (SYK) and CXCL17, were expressed approximately 100-fold higher. This data was further evaluated against bulk RNA isolated from HIV-infected human primary CD4 + T cells. A nearly 6-fold higher expression of SYK mRNA was observed in DMSO-treated CD4 + T cells compared to those stimulated with PMA/Ionomycin.</p><p><strong>Conclusion: </strong>This study found that the CosMx SMI platform is valuable for assessing HIV infection and providing insights into host biomarkers associated with HIV reservoirs. Higher relative expression of the SYK gene in aviremic-infected cells from the humanized mouse HIV model was consistent with levels found in CD4 + T cells of aviremic donors.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"116"},"PeriodicalIF":9.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing identifies a subtype of FN1 + tumor-associated macrophages associated with glioma recurrence and as a biomarker for immunotherapy.","authors":"Houshi Xu, Huihui Chai, Ming Chen, Ruize Zhu, Shan Jiang, Xiaoyu Liu, Yue Wang, Jiawen Chen, Junji Wei, Ying Mao, Zhifeng Shi","doi":"10.1186/s40364-024-00662-1","DOIUrl":"https://doi.org/10.1186/s40364-024-00662-1","url":null,"abstract":"<p><strong>Background: </strong>Glioma is the most common primary malignant tumor in the brain, and even with standard treatments including surgical resection, radiotherapy, and chemotherapy, the long-term survival rate of patients remains unsatisfactory. Recurrence is one of the leading causes of death in glioma patients. The molecular mechanisms underlying glioma recurrence remain unclear.</p><p><strong>Methods: </strong>Our study utilized single-cell sequencing, spatial transcriptomics, and RNA-seq data to identify a subtype of FN1 + tumor-associated macrophages (FN1 + TAMs) associated with glioma recurrence.</p><p><strong>Results: </strong>This study revealed an increased abundance of FN1 + TAMs in recurrent gliomas, indicating their potential involvement as a critical factor in glioma recurrence. A negative correlation was observed between the abundance of FN1 + TAMs in primary gliomas and the interval time to recurrence, suggesting poor prognosis for glioma patients with high levels of FN1 + TAMs. Further investigation showed that FN1 + TAMs were enriched in hypoxic tumor regions, implying that metabolic changes in tumors drive the production and recruitment of FN1 + TAMs. Additionally, FN1 + TAMs were found to contribute to the regulation of an immunosuppressive microenvironment in gliomas, and their abundance might serve as an indicator of patients' sensitivity to immunotherapy. Finally, we developed a user-friendly website, PRIMEG ( http://www.szflab.site/PRIMEG/ ), for exploring the immune microenvironment of primary and recurrent gliomas.</p><p><strong>Conclusion: </strong>Our findings highlight a subtype of FN1 + TAMs associated with glioma recurrence, providing new insights into potential therapeutic targets. Moreover, the abundance of FN1 + TAMs hold promise for predicting immune therapy response and aiding in more precise risk stratification of recurrent glioma patients.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"114"},"PeriodicalIF":9.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The significant others of aurora kinase a in cancer: combination is the key.","authors":"Kumar Nikhil, Kavita Shah","doi":"10.1186/s40364-024-00651-4","DOIUrl":"https://doi.org/10.1186/s40364-024-00651-4","url":null,"abstract":"<p><p>AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"109"},"PeriodicalIF":9.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142332256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma.","authors":"Jun Jiang, Chao Xu, Donghui Han, Yuan Lu, Fa Yang, Jiawei Wang, Xiaolong Yan, Xiaorong Mu, Jipeng Zhang, Chenghui Jia, Xinyao Xu, Kui Liu, Zhenhua Liu, Li Gong, Yi Wan, Qiang Lu","doi":"10.1186/s40364-024-00656-z","DOIUrl":"https://doi.org/10.1186/s40364-024-00656-z","url":null,"abstract":"<p><p>Novel neoadjuvant immunotherapy combined with chemotherapy (neoICT) has improved outcomes for patients with esophageal squamous-cell carcinoma (ESCC), but challenges persist in low response rates and therapy resistance. Little is known about the intra-tumoral heterogeneity in the ESCC tumor microenvironment (TME) that underlies differential responses to neoadjuvant therapy. We applied single-cell RNA sequencing (scRNA-seq) profiling and multiplexed immunofluorescence staining to thoroughly decipher the TME in ESCC specimens from a neoadjuvant anti-PD1 combination therapy clinical trial. The cancer-associated fibroblasts (CAFs) population showed the significant alteration in abundance following neoadjuvant therapy. Specifically, IL6 + CCL2 + immunomodulatory CAFs and a novel CD248 + mechanoresponsive CAFs subset exhibited increasing infiltration. Mechanistically, CD248 + mechanoresponsive CAFs approached and lined the tumor nest to physically block the infiltration of CD8 + T cells and drug delivery, while IL6 + CCL2 + immunomodulatory CAFs induced therapeutic resistance with distinct IL-6 expression. Among patients treated with neoICT, we observed prominent CAF-T cell interactions. In particular, the NECTIN2-TIGIT ligand-receptor pair was enriched in treated samples, and TIGIT was identified as the major inhibitory checkpoint of T cells. Our findings demonstrate distinct alterations in TME constituent responses to neoadjuvant immunotherapy and identify functional phenotypes of CAFs associated with unfavorable therapeutic responses in patients. This provides potential targets to enhance responses to neoadjuvant therapy in ESCC.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"12 1","pages":"113"},"PeriodicalIF":9.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142332253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}