{"title":"Spatial proteogenomic profiling uncovers sensitization strategies for antibody-drug conjugate in HER2-positive breast cancer.","authors":"Yu-Wen Cai, Shu-Han Jia, Hao Wang, Hong Hu, Yan-Wu Zhang, Zhi-Ming Shao, Han-Dong Sun, Ke-Da Yu","doi":"10.1016/j.xcrm.2026.102987","DOIUrl":"10.1016/j.xcrm.2026.102987","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) have transformed the treatment of HER2-positive breast cancer, yet resistance remains poorly understood. Using imaging mass cytometry, we profiled 157 regions of interest comprising 912,360 single cells from 47 HER2-positive/hormone receptor-negative breast cancers treated with SHR-A1811 in the FASCINATE-N trial. Spatial proteomic analyses identified two determinants of ADC response: elevated tumor-cell H3K27ac expression was associated with improved ADC efficacy, whereas collagen-positive fibroblasts mediated resistance. Combining ADC with the histone deacetylase inhibitor chidamide or the collagen-modulating agent losartan produced synergistic antitumor effects in preclinical models. These biomarkers and therapeutic vulnerabilities were independently validated in patients with advanced HER2-positive disease receiving trastuzumab deruxtecan. Moreover, based on these spatial features, we developed a clinically applicable ADC barrier prediction model that can be implemented using multiplex immunofluorescence. Taken together, our findings reveal actionable spatial determinants of ADC efficacy and suggest potential combination therapeutic strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102987"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-19DOI: 10.1016/j.xcrm.2026.103004
Zachary T Mack, Margarita Yastrebova, Chang-Uk Lim, Xiaokai Ding, Jing Li, Alvina Khamidullina, Amanda C Sharko, Michael Saint-Antoine, Thomas A Hilimire, Gary P Schools, Kaitlyn Digsby, Amanda Eckstrom, Erin Belcher, Gwenael Madiot, Hao Ji, Vitali Sikirzhitski, Chao Cai, Guoshuai Cai, Abhyudai Singh, Victor Tatarskiy, Mengqian Chen, Igor B Roninson, Eugenia V Broude
{"title":"CDK8/19 inhibition prevents adaptive resistance to CDK4/6 inhibitors in vitro and in vivo.","authors":"Zachary T Mack, Margarita Yastrebova, Chang-Uk Lim, Xiaokai Ding, Jing Li, Alvina Khamidullina, Amanda C Sharko, Michael Saint-Antoine, Thomas A Hilimire, Gary P Schools, Kaitlyn Digsby, Amanda Eckstrom, Erin Belcher, Gwenael Madiot, Hao Ji, Vitali Sikirzhitski, Chao Cai, Guoshuai Cai, Abhyudai Singh, Victor Tatarskiy, Mengqian Chen, Igor B Roninson, Eugenia V Broude","doi":"10.1016/j.xcrm.2026.103004","DOIUrl":"10.1016/j.xcrm.2026.103004","url":null,"abstract":"<p><p>Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a standard of care for estrogen receptor-positive breast cancer and are being developed for other malignancies. However, resistance to these drugs readily develops, limiting their impact on patient survival. Mechanisms of resistance to CDK4/6 inhibition involve multiple changes in gene expression. We investigated the process of tumor cell adaptation to CDK4/6 inhibitors and the impact of selective inhibitors of CDK8/19 Mediator kinases-broad-spectrum regulators of transcriptional reprogramming-on such adaptations. Adaptive non-genetic resistance to CDK4/6 inhibitors develops rapidly, but the addition of CDK8/19 inhibitors prevents the development of this resistance in different tumor models, in vitro and in vivo. RNA sequencing (RNA-seq) analysis reveals that combining CDK4/6 and CDK8/19 inhibitors suppresses many of the adaptation-associated changes in gene expression, including those previously associated with CDK4/6 inhibitor resistance. The findings suggest that CDK8/19 inhibition may greatly extend the therapeutic benefit of CDK4/6 inhibitors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103004"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-09-01DOI: 10.1016/j.xcrm.2026.103007
Anna Samarra, Alejandro J Alcañiz, Narciso M Quijada, Simone Renwick, Sergio George, Trishla Sinha, Cecília Martínez-Costa, Nicola Segata, Alexandra Zhernakova, Lars Bode, Maria Carmen Collado
{"title":"Maternal secretor status and human milk oligosaccharides influence the infant gut resistome.","authors":"Anna Samarra, Alejandro J Alcañiz, Narciso M Quijada, Simone Renwick, Sergio George, Trishla Sinha, Cecília Martínez-Costa, Nicola Segata, Alexandra Zhernakova, Lars Bode, Maria Carmen Collado","doi":"10.1016/j.xcrm.2026.103007","DOIUrl":"10.1016/j.xcrm.2026.103007","url":null,"abstract":"<p><p>The infant gut resistome is established early in life and is shaped by perinatal exposures, yet the mechanisms underlying its modulation remain unclear. We combined shotgun metagenomics of fecal samples from 57 one-month-old infants and paired milk samples from 50 mothers in the MAMI cohort to investigate the influence of maternal secretor status on early-life resistome development. Longitudinal follow-up at 6 and 12 months, and also further validation in the independent Lifelines NEXT (LLNEXT) cohort, support our findings. Cesarean section (C-section) was associated with increased antibiotic resistance gene (ARG) diversity, whereas exclusive breastfeeding reduced ARG abundance and diversity. Maternal secretor status further modified resistome composition among exclusively breastfed infants. Human milk oligosaccharide profiling identified specific glycans underlying these associations, with 2'-fucosyllactose and 6'-sialyllactose showing negative correlations with distinct ARG classes. These findings identify human milk composition as a key determinant of early-life resistome assembly and a potential target for modulating antimicrobial resistance.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103007"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-09-01DOI: 10.1016/j.xcrm.2026.103018
Xiao Liu, Maorong Zhu, Cheng Zou, Zhengcong Cao, Yawen Wang, Guangzhao Yang, Xiaolin Liu, Yuxin Wu, Duo Yu, Dan Zheng, Kuo Zhang, Juan Li, Wangqian Zhang, Shuning Wang, Haozhe Qin, Qiang Hao, Yingqi Zhang, Anan Yin, Yalong He, Lei He, Xiaonan Luo, Wei Lin, Meng Li, Jintao Gu
{"title":"CRISPRa-identified transcription factors reprogram glioblastoma into dendritic cell-like cells to elicit systemic antitumor immunity.","authors":"Xiao Liu, Maorong Zhu, Cheng Zou, Zhengcong Cao, Yawen Wang, Guangzhao Yang, Xiaolin Liu, Yuxin Wu, Duo Yu, Dan Zheng, Kuo Zhang, Juan Li, Wangqian Zhang, Shuning Wang, Haozhe Qin, Qiang Hao, Yingqi Zhang, Anan Yin, Yalong He, Lei He, Xiaonan Luo, Wei Lin, Meng Li, Jintao Gu","doi":"10.1016/j.xcrm.2026.103018","DOIUrl":"10.1016/j.xcrm.2026.103018","url":null,"abstract":"<p><p>Although immunotherapy has transformed the treatment landscape for many types of cancer, its therapeutic efficacy in glioblastoma (GBM) is limited by insufficient antigen presentation and the immunogenic cell exclusion in the tumor microenvironment. Here, we develop a candidate-based CRISPR activation (CRISPRa) functional screen to identify regulators of conventional dendritic cell (cDC)-fate specification. We determine that the transcription factors Zfp366/Znf366, Pu.1, Irf8, and Batf3 (ZPIB) are sufficient to convert GBM cells into cDC-like cells. ZPIB-mediated reprogramming results in global transcriptional and epigenetic remodeling in glioma cells. Single-cell RNA sequencing (scRNA-seq) profiling also reveals efficient and dynamic reprogramming of GBM cells to cDCs in vivo. Moreover, reprogrammed tumor cells remodel the microenvironment and elicit systemic tumor-eradicating and durable antitumor immunity in multiple mouse GBM models. Antitumor immunity elicited by ZPIB-DCs is synergistic with immune checkpoint inhibitors. Finally, we evaluate the clinical applicability of this approach by generating ZPIB-DCs from GBM patients within a humanized model. Our study represents a cellular reprogramming therapeutic strategy with broad implications for clinical immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103018"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-21DOI: 10.1016/j.xcrm.2026.103000
Tobias Hegelmaier, Jeremias Motte, Denise Walther, Eugen Feist, Alexander Duscha, Christiane Desel, Vaia Pappa, Martin Böttcher, Marvin Voigt, Melissa Sgodzai, Marwa Al-Dubai, Roland Schroers, Dominic Borie, Georg Schett, Dimitrios Mougiakakos, Ralf Gold, Aiden Haghikia
{"title":"Long-term outcomes of anti-CD19 CAR T cell therapy in refractory myasthenia gravis: A case series.","authors":"Tobias Hegelmaier, Jeremias Motte, Denise Walther, Eugen Feist, Alexander Duscha, Christiane Desel, Vaia Pappa, Martin Böttcher, Marvin Voigt, Melissa Sgodzai, Marwa Al-Dubai, Roland Schroers, Dominic Borie, Georg Schett, Dimitrios Mougiakakos, Ralf Gold, Aiden Haghikia","doi":"10.1016/j.xcrm.2026.103000","DOIUrl":"10.1016/j.xcrm.2026.103000","url":null,"abstract":"<p><p>Anti-CD19 CAR T cell therapy represents an emerging therapeutic approach for generalized, treatment-refractory myasthenia gravis (MG), a predominantly B-cell-mediated autoimmune disease for which durable treatment-free remission remains an unmet clinical goal. Despite recent advances, current targeted therapies generally require lifelong repeated administration and rarely induce durable treatment-free remission. We report on three patients with severe, treatment-resistant MG, including one patient with concomitant rheumatoid arthritis, treated with autologous, fully human anti-CD19 CAR T cells. All three patients achieve rapid, sustained clinical MG remission for at least 19 months, allowing discontinuation of MG-specific immunotherapies and substantial improvement in clinical and functional outcomes despite persistent detectable anti-AChR autoantibody titers. B cell depletion is profound, and treatment-related adverse events remain transient and manageable during long-term follow-up. These data support anti-CD19 CAR T cell therapy as a durable, effective intervention for refractory MG and warrant further evaluation in prospective controlled clinical trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103000"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-19DOI: 10.1016/j.xcrm.2026.102993
Brandon M Sie, Yumei Leng, Nadege Nziza, Moriah M Mitchell, Nicholas E Webb, Yunjoo Lee, Sunni L Mumford, Enrique F Schisterman, H Benjamin Larman, Boris Julg, Galit Alter, Stephen J Elledge
{"title":"Humoral pregnancy analyses reveal strategies for fetal protection and aberrancy in miscarriage.","authors":"Brandon M Sie, Yumei Leng, Nadege Nziza, Moriah M Mitchell, Nicholas E Webb, Yunjoo Lee, Sunni L Mumford, Enrique F Schisterman, H Benjamin Larman, Boris Julg, Galit Alter, Stephen J Elledge","doi":"10.1016/j.xcrm.2026.102993","DOIUrl":"10.1016/j.xcrm.2026.102993","url":null,"abstract":"<p><p>The maternal immune system must simultaneously defend against pathogens with tolerance of the antigenically distinct fetus. Despite the central importance of immune modulation during pregnancy, epitope-level analyses of the maternal antibody repertoire remain lacking. Here, we performed high-throughput, multi-isotype longitudinal serology of 119 women from preconception through pregnancy, combining phage display of linear peptides with whole protein-based antigen assays to profile antibody responses to viral and self-antigens. We observed a broad expansion of the maternal IgG repertoire and a relative increase in IgA titers, both tracking with pregnancy progression. These changes may augment transplacental and mucosal immunity in the fetus and newborn, respectively. Notably, pregnancies ending in miscarriage exhibited pronounced IgA titer spikes against both viral and self-antigens unrelated to active infection (sensitivity 14/19, 74%, specificity 95%), indicating an underlying immune perturbation may precede pregnancy loss.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102993"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cortical-to-pallidal beta cascade underlies network pathophysiology in Parkinson's disease.","authors":"Jeong Woo Choi, Amirreza Alijanpourotaghsara, Koorosh Mirpour, Sahil Chilukuri, Nader Pouratian","doi":"10.1016/j.xcrm.2026.103001","DOIUrl":"10.1016/j.xcrm.2026.103001","url":null,"abstract":"<p><p>Parkinson's disease (PD) motor symptoms are linked to excessive beta band (13-35 Hz) oscillations and basal ganglia-cortical (BGC) synchrony, yet their dynamic inter-relation remains unclear. Based on computational modeling, we hypothesize that transient high-beta (20-35 Hz) BGC coupling induces subcortical low-beta (13-20 Hz) amplification. We recorded intraoperative neural signals from the globus pallidus internus and externus (GPi and GPe, respectively) and motor cortex (M1) in 23 PD patients during deep brain stimulation implantation. High-beta bursts in M1 and GPe were classified as either temporally synchronized or isolated. Synchronous M1-GPe high-beta bursts led by GPe were followed by GPi low-beta amplification, which were not evident with either isolated M1 high-beta bursts or M1-led synchronous bursts. Dopaminergic medication attenuated this GPi low-beta amplification and improved symptoms. These findings suggest that excessive M1 high-beta bursts following GPe high-beta activity trigger a cascade establishing low-beta propagation to GPi, which may contribute to PD motor dysfunction.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"103001"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-19DOI: 10.1016/j.xcrm.2026.102998
Yichen Zhu, Jiaji Yu, Yu Jeong Kim, Yanxin Tian, Zhe Li, Yuning Chen, Zibai Lyu, Enbo Zhu, Annabel S Zhao, Nathan Ma, Catherine Zhang, Adam Kramer, Matthew Wilson, Ryan Hon, Yu-Chen Wang, Siyu Lin, Xinyuan Shen, Zoe Hahn, Yuchong Zhang, Aijun Wang, Yan-Ruide Li, Lili Yang
{"title":"Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors.","authors":"Yichen Zhu, Jiaji Yu, Yu Jeong Kim, Yanxin Tian, Zhe Li, Yuning Chen, Zibai Lyu, Enbo Zhu, Annabel S Zhao, Nathan Ma, Catherine Zhang, Adam Kramer, Matthew Wilson, Ryan Hon, Yu-Chen Wang, Siyu Lin, Xinyuan Shen, Zoe Hahn, Yuchong Zhang, Aijun Wang, Yan-Ruide Li, Lili Yang","doi":"10.1016/j.xcrm.2026.102998","DOIUrl":"10.1016/j.xcrm.2026.102998","url":null,"abstract":"<p><p>Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T (<sup>Allo</sup>ESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. <sup>Allo</sup>ESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, <sup>Allo</sup>ESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived <sup>Allo</sup>ESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of <sup>Allo</sup>ESO-T cells across solid tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102998"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-09-15Epub Date: 2026-08-18DOI: 10.1016/j.xcrm.2026.102994
Dolly Jain, Nishant Pandey, Somesh K Jha, Shreya Sinha, Ragini Singh, Junaid Alam, Bharti Aggarwal, Neelam Chauhan, Arunima Acharya, Anu P V, Vandana Dhangar, Ritika Bhargava, Nikhil K Chourasiya, Ali Khan, Arnab K Sahoo, Debasish Nath, Lalita Mehra, Kajal Rana, Poonam Yadav, Jahanvi Ralhan, Saroj Rajput, Asish Pal, Arindam Maitra, Santiswarup Singha, Rajesh Panwar, Satish Khurana, Ujjaini Dasgupta, Sandeep K Bhoriwal, Jyothi S Prabhu, Prasenjit Das, Veena S Patil, Avinash Bajaj
{"title":"Targeting of tripartite neuron-cancer-immune cell crosstalk augments response to chemotherapy and immunotherapy.","authors":"Dolly Jain, Nishant Pandey, Somesh K Jha, Shreya Sinha, Ragini Singh, Junaid Alam, Bharti Aggarwal, Neelam Chauhan, Arunima Acharya, Anu P V, Vandana Dhangar, Ritika Bhargava, Nikhil K Chourasiya, Ali Khan, Arnab K Sahoo, Debasish Nath, Lalita Mehra, Kajal Rana, Poonam Yadav, Jahanvi Ralhan, Saroj Rajput, Asish Pal, Arindam Maitra, Santiswarup Singha, Rajesh Panwar, Satish Khurana, Ujjaini Dasgupta, Sandeep K Bhoriwal, Jyothi S Prabhu, Prasenjit Das, Veena S Patil, Avinash Bajaj","doi":"10.1016/j.xcrm.2026.102994","DOIUrl":"10.1016/j.xcrm.2026.102994","url":null,"abstract":"<p><p>We report presence of cholinergic nerve fibers in the periphery and stroma of colon cancer tissues and their correlation with poor T cell and increased macrophage infiltration. We employed hydrogel-mediated localized delivery of an FDA-approved local anesthetic, bupivacaine (BUP), to target acetylcholine (ACh)-mediated crosstalk of cholinergic neurons with cancer and immune cells. Localized BUP-Gel therapy promotes T cell-mediated tumor inhibition and enhances the antitumor response of systemic chemotherapy and immunotherapy. Further, blockade of cancer- and immune cell-specific ACh receptors inhibits tumor growth, alters the TME, and augments the impact of chemotherapy and immunotherapy. Finally, we demonstrate that ACh receptor antagonists polarize macrophages toward an M1-like phenotype and activate T cell immunity in tumor explants of patients. Therefore, targeting cholinergic signals through localized delivery of anesthetics, as well as direct immune reprogramming via cholinergic receptor antagonists, may provide a means to modulate this tripartite crosstalk, with potential implications for therapeutic strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102994"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Symptoms and treatment response to florensocatib and inhaled tobramycin in bronchiectasis: Post hoc analysis of two randomized trials.","authors":"Yong-Hua Gao, Xue-Shan Li, Xiao-Li Sun, Fang-Qiong Li, Lu-Yin Sun, Han-Mo Liu, Wei-Jie Guan","doi":"10.1016/j.xcrm.2026.102995","DOIUrl":"10.1016/j.xcrm.2026.102995","url":null,"abstract":"<p><p>Inhaled antibiotics and DPP-1 inhibitors improve clinical outcomes in bronchiectasis, but whether baseline symptom burden predicts differential treatment responses remains unclear. In this post hoc analysis of two multicenter randomized trials (SAVE-BE, n = 224; TORNASOL, n = 357), we evaluate the association between baseline Quality of Life-Bronchiectasis Respiratory Symptom Scale (QoL-B-RSS) and treatment effects of florensocatib and inhaled tobramycin. In SAVE-BE, florensocatib reduces exacerbation rates versus placebo (relative risk [RR], 0.47; 95% confidence interval [CI], 0.33-0.67; p < 0.0001), with RRs of 0.53 and 0.40 observed in patients with high and low symptom burdens, respectively, but no significant symptomatic improvement. In TORNASOL, tobramycin produces clinically meaningful QoL-B-RSS improvements (exceeding the 8-point cutoff in high-symptom patients) and ameliorates bronchitic symptoms, with greater benefits in those with higher baseline symptom burden. These hypothesis-generating findings suggest that baseline symptom burden may identify differential responses to anti-inflammatory versus anti-infective therapies in bronchiectasis and support its potential as a simple, practical stratification tool to guide personalized treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102995"},"PeriodicalIF":14.0,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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