Hematological malignancies of B cell origin are characterized by frequent expression of CXCR4. The CXCR4-CXCL12 axis facilitates the in vivo dissemination of B cell lymphoma and multiple myeloma (MM). It is also a pivotal regulator in the migration and bone marrow homing of T cells. Herein, we hypothesized that engineering CAR-T cells to overexpress CXCR4 could utilize the CXCR4-CXCL12 axis to enhance their therapeutic efficacy by increasing tumor tracking and bone marrow accumulation. In this study, we found that lentiviral transduction caused significant CXCR4 downregulation on T cells, leading to impaired CAR-T cell migration to CXCL12. By contrast, CXCR4 overexpressing (CXCR4hi) CD19 CAR-T cells and BCMA CAR-T cells showed superior in vivo tumor tracking and clearance capacities in the localized and systemically disseminated models of B cell lymphoma and MM, respectively. Notably, CXCR4 modification significantly facilitated the bone marrow homing and accumulation of CAR-T cells, which further promoted memory T cell differentiation, persistence and prolonged antitumor activity. Building on these findings, an investigator-initiated clinical trial (IIT) evaluating CXCR4hi CD19 CAR-T cells in patients with relapsed/refractory B cell malignancies (NCT04684472) achieved encouraging efficacy: the low-dose cohort yielded 3 complete responses (CRs) and 1 partial response (PR) within the first month post-infusion. These findings support the use of CXCR4 modification as a strategy to improve CAR-T cell efficacy in treating hematologic B cell malignancies, warranting further clinical investigation.
{"title":"CXCR4-modification enhances CAR-T efficacy by improving tumor tracking and bone marrow homing in B-cell malignancies.","authors":"Pei Shu,Fuchun Guo,Diyuan Qin,Liqun Zou,Qizhi Ma,Benxia Zhang,Ge Gao,Yue Chen,Xia He,Ming Jiang,Ning Liu,Kexun Zhou,Jian Zhao,Yanna Lei,Yu Gao,Yugu Zhang,Yao Zeng,Mingyang Feng,Xiaoyu Li,Dan Li,Yongsheng Wang","doi":"10.1038/s41392-025-02522-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02522-2","url":null,"abstract":"Hematological malignancies of B cell origin are characterized by frequent expression of CXCR4. The CXCR4-CXCL12 axis facilitates the in vivo dissemination of B cell lymphoma and multiple myeloma (MM). It is also a pivotal regulator in the migration and bone marrow homing of T cells. Herein, we hypothesized that engineering CAR-T cells to overexpress CXCR4 could utilize the CXCR4-CXCL12 axis to enhance their therapeutic efficacy by increasing tumor tracking and bone marrow accumulation. In this study, we found that lentiviral transduction caused significant CXCR4 downregulation on T cells, leading to impaired CAR-T cell migration to CXCL12. By contrast, CXCR4 overexpressing (CXCR4hi) CD19 CAR-T cells and BCMA CAR-T cells showed superior in vivo tumor tracking and clearance capacities in the localized and systemically disseminated models of B cell lymphoma and MM, respectively. Notably, CXCR4 modification significantly facilitated the bone marrow homing and accumulation of CAR-T cells, which further promoted memory T cell differentiation, persistence and prolonged antitumor activity. Building on these findings, an investigator-initiated clinical trial (IIT) evaluating CXCR4hi CD19 CAR-T cells in patients with relapsed/refractory B cell malignancies (NCT04684472) achieved encouraging efficacy: the low-dose cohort yielded 3 complete responses (CRs) and 1 partial response (PR) within the first month post-infusion. These findings support the use of CXCR4 modification as a strategy to improve CAR-T cell efficacy in treating hematologic B cell malignancies, warranting further clinical investigation.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"7 1","pages":"38"},"PeriodicalIF":39.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer cells orchestrate a highly dynamic and interconnected network spanning metabolic, epigenetic, and immune mechanisms to drive adaptive plasticity and continuous development. This review synthesizes emerging insights into the coevolutionary strategies employed by malignant and stromal cells-particularly tumor cells and immune populations-across the continuum of tumorigenesis, metastasis, and treatment resistance. During tumor initiation, cancer cells rewire metabolism and generate oncometabolites that reshape the chromatin architecture to support immune evasion. Concurrently, metabolic competition in the tumor microenvironment (TME) induces epigenetic exhaustion of cytotoxic T cells, whereas tumor-associated myeloid cells adopt immunosuppressive and angiogenic phenotypes via metabolite-dependent histone modifications to promote carcinogenesis. At metastatic frontiers, under the local metabolic pressure of target organs, tumor cells undergo epigenetic reprogramming to evade immune attacks and support colonization. Premetastatic niches are preconditioned through exosome-mediated transfer of metabolic enzymes and noncoding RNAs that reprogram resident cells before tumor cells arrive. In cancer immunotherapy, tumors often exploit metabolic adaptative strategies to inhibit cell death signaling pathways or the compensatory activation of self-protective mechanisms to circumvent immune-mediated cytotoxicity and develop resistance to immunotherapy. By mapping these dynamic interactions, we propose a novel conceptual framework of the "metabolic-epigenetic-immune axis" that transcends traditional compartmentalized approaches and helps to identify nodal convergence points for therapeutic co-targeting. This review also prioritizes multitarget inhibitors arising from the convergence of metabolic reprogramming, epigenetic plasticity, and immune evasion networks. An integrated approach to these pathways advances next-generation precision oncology strategies aimed at circumventing the evolutionary resilience of cancer.
{"title":"Targeting metabolic-epigenetic-immune axis in cancer: molecular mechanisms and therapeutic implications.","authors":"Xing Wang,Xiyuan Luo,Ruiling Xiao,Xiaohong Liu,Feihan Zhou,Decheng Jiang,Jialu Bai,Ming Cui,Lei You,Yupei Zhao","doi":"10.1038/s41392-025-02334-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02334-4","url":null,"abstract":"Cancer cells orchestrate a highly dynamic and interconnected network spanning metabolic, epigenetic, and immune mechanisms to drive adaptive plasticity and continuous development. This review synthesizes emerging insights into the coevolutionary strategies employed by malignant and stromal cells-particularly tumor cells and immune populations-across the continuum of tumorigenesis, metastasis, and treatment resistance. During tumor initiation, cancer cells rewire metabolism and generate oncometabolites that reshape the chromatin architecture to support immune evasion. Concurrently, metabolic competition in the tumor microenvironment (TME) induces epigenetic exhaustion of cytotoxic T cells, whereas tumor-associated myeloid cells adopt immunosuppressive and angiogenic phenotypes via metabolite-dependent histone modifications to promote carcinogenesis. At metastatic frontiers, under the local metabolic pressure of target organs, tumor cells undergo epigenetic reprogramming to evade immune attacks and support colonization. Premetastatic niches are preconditioned through exosome-mediated transfer of metabolic enzymes and noncoding RNAs that reprogram resident cells before tumor cells arrive. In cancer immunotherapy, tumors often exploit metabolic adaptative strategies to inhibit cell death signaling pathways or the compensatory activation of self-protective mechanisms to circumvent immune-mediated cytotoxicity and develop resistance to immunotherapy. By mapping these dynamic interactions, we propose a novel conceptual framework of the \"metabolic-epigenetic-immune axis\" that transcends traditional compartmentalized approaches and helps to identify nodal convergence points for therapeutic co-targeting. This review also prioritizes multitarget inhibitors arising from the convergence of metabolic reprogramming, epigenetic plasticity, and immune evasion networks. An integrated approach to these pathways advances next-generation precision oncology strategies aimed at circumventing the evolutionary resilience of cancer.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"28"},"PeriodicalIF":39.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1038/s41392-025-02531-1
Chunmei Cai,Guohua Ni,Lei Chen,Cheng Deng,Shengjun Chai,Rui Wang,Rong Zhang,Fengming Luo,Ri-Li Ge
At high altitudes, which typically exceed 2500 m, approximately 80 million people reside permanently, with over a million visitors annually. The primary effect of high altitude is hypobaric hypoxia, which leads to decreased oxygen availability and a cascade of physiological responses. However, inadequate or excessive responses can lead to malacclimatization, resulting in hypoxemia and various high-altitude illnesses, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and high-altitude pulmonary hypertension (HAPH). Acute altitude illnesses (AMS, HACE, and HAPE) stem from inadequate acclimatization, whereas chronic conditions (CMS and HAPH) reflect prolonged or excessive adaptive responses. This review briefly summarizes the current knowledge on the clinical manifestations, epidemiology, and risk factors for high-altitude diseases. Additionally, this review systematically discusses the most recent pathophysiological mechanisms underlying these conditions, with a special emphasis on genetic susceptibility and chronic altitude illness (CMS and HAPH). Furthermore, a comprehensive overview of current prevention and treatment strategies is provided, emphasizing the promising effects of natural medicines, especially traditional Tibetan medicines. Despite extensive research, the exact mechanisms underlying these illnesses remain elusive, and options for their management are still limited. This review aims to provide novel insights into the pathogenic mechanisms of these complex conditions and guide future research directions to improve the prevention and management of high-altitude illnesses.
{"title":"Altitude hypoxia and hypoxemia: pathogenesis and management.","authors":"Chunmei Cai,Guohua Ni,Lei Chen,Cheng Deng,Shengjun Chai,Rui Wang,Rong Zhang,Fengming Luo,Ri-Li Ge","doi":"10.1038/s41392-025-02531-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02531-1","url":null,"abstract":"At high altitudes, which typically exceed 2500 m, approximately 80 million people reside permanently, with over a million visitors annually. The primary effect of high altitude is hypobaric hypoxia, which leads to decreased oxygen availability and a cascade of physiological responses. However, inadequate or excessive responses can lead to malacclimatization, resulting in hypoxemia and various high-altitude illnesses, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and high-altitude pulmonary hypertension (HAPH). Acute altitude illnesses (AMS, HACE, and HAPE) stem from inadequate acclimatization, whereas chronic conditions (CMS and HAPH) reflect prolonged or excessive adaptive responses. This review briefly summarizes the current knowledge on the clinical manifestations, epidemiology, and risk factors for high-altitude diseases. Additionally, this review systematically discusses the most recent pathophysiological mechanisms underlying these conditions, with a special emphasis on genetic susceptibility and chronic altitude illness (CMS and HAPH). Furthermore, a comprehensive overview of current prevention and treatment strategies is provided, emphasizing the promising effects of natural medicines, especially traditional Tibetan medicines. Despite extensive research, the exact mechanisms underlying these illnesses remain elusive, and options for their management are still limited. This review aims to provide novel insights into the pathogenic mechanisms of these complex conditions and guide future research directions to improve the prevention and management of high-altitude illnesses.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"86 1","pages":"27"},"PeriodicalIF":39.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.
由于支持转换疗法疗效的证据有限，转换疗法仍然是治疗不可切除肝细胞癌（uHCC）的一种不常见策略。为了解决这一差距，我们启动了一项前瞻性2期多中心试验（NCT04997850），比较lenvatinib联合lenvatinib、经动脉化疗栓塞（TACE）和PD-1抑制剂与单独TACE治疗肝癌患者的LEN-TAP方案。该研究的主要结局是挽救性肝切除（SLR）率；次要指标包括客观缓解率（ORR）、总生存期（OS）、无事件生存期（EFS）、无复发生存期（RFS）和安全性。从2020年10月到2021年11月，142名符合条件的参与者被分配到LEN-TAP （n = 71）或TACE单药治疗（n = 71）。在中位随访24.2个月时，LEN-TAP队列显示出更高的SLR率（59.2% vs. 18.3%, P < 0.001）和ORR （78.9% vs. 16.9%, P < 0.001）。LEN-TAP队列的中位OS、EFS和RFS也显著延长（未达到vs. 23.0个月，P < 0.001; 20.03 vs. 6.52个月，P < 0.001; 36.6 vs. 19.0个月，P = 0.048）。尽管LEN-TAP治疗相关的3级不良事件发生率更高（60.6% vs. 21.1%, P < 0.001），但未观察到4级或更高级别的毒性。通过单细胞测序和流式细胞术进行的探索性生物标志物评估将循环HLA-DR+CD38+CD8+ T细胞水平升高与改善的治疗反应联系起来。这些T细胞似乎通过CXCR6-PI3K-AKT信号轴潜在地介导抗肿瘤活性。总之，LEN-TAP方案显示出有希望的疗效和可接受的耐受性，作为uHCC的转化治疗，外周HLA-DR+CD38+CD8+ T细胞丰度可作为治疗获益的潜在预测因子。
{"title":"Lenvatinib plus transarterial chemoembolization and PD-1 inhibitors as conversion therapies for unresectable intermediate-advanced hepatocellular carcinoma: a phase 2 trial and exploratory biomolecular study.","authors":"Xiaoyun Zhang,Haozheng Cai,Wei Peng,Haiqing Wang,JiaYi Wu,Xinrui Zhu,Weixin Guo,Fei Xie,Yu Zhang,Ming Wang,Yu Yu,Yongjie Zhou,Chuan Li,Junyi Shen,Chang Liu,Yu Yang,Xiaozhong Jiang,Qiu Li,Weixia Chen,Yujun Shi,Wusheng Lu,Xin Sun,Xielin Feng,Maolin Yan,Shuqun Cheng,Tianfu Wen","doi":"10.1038/s41392-025-02498-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02498-z","url":null,"abstract":"Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR+CD38+CD8+ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR+CD38+CD8+ T cell abundance serving as a potential predictor of therapeutic benefit.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":"37"},"PeriodicalIF":39.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Osimertinib inhibits the MYLK4-mediated phosphorylation of CDKAL1 to suppress stemness and chemoresistance in rhabdomyosarcoma.","authors":"Takuto Itano,Rongsheng Huang,Toshifumi Ozaki,Eiji Nakata,Atsushi Fujimura","doi":"10.1038/s41392-025-02548-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02548-6","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"258 1","pages":"26"},"PeriodicalIF":39.3,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework-integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization-to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.
{"title":"Multiomics Mendelian randomization identifies serpin family G member 1 as a chronic obstructive pulmonary disease modulator.","authors":"Erkang Yi,Jieda Cui,Hairong Wang,Fan Wu,Qiyang Hong,Qingyang Li,Chengshu Xie,Huahua Xu,Yu Liu,Xinru Ran,Xiaohui Wu,Qi Wan,Gaoying Tang,Leqing Zhu,Junling Pang,Yumin Zhou,Erping Long,Pixin Ran","doi":"10.1038/s41392-025-02547-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02547-7","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework-integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization-to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":"34"},"PeriodicalIF":39.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1038/s41392-025-02546-8
Ugo Chianese, Chiara Papulino, Gerardo Saggese, Ahmad Ali, Marianna Ciotola, Enza Lonardo, Mirko Cortese, Gregorio Favale, Annabella Di Mauro, Danila La Gioia, Valentina Golino, Eduardo Sommella, Pietro Campiglia, Renato Franco, Fortunato Ciardiello, Ferdinando De Vita, Vincenzo Carafa, Lucia Altucci, Rosaria Benedetti
Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach-including metabolomics, proteomics, and lipidomics-was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.
{"title":"Glycolytic heterogeneity drives metabolic-targeted therapy in pancreatic ductal adenocarcinoma.","authors":"Ugo Chianese, Chiara Papulino, Gerardo Saggese, Ahmad Ali, Marianna Ciotola, Enza Lonardo, Mirko Cortese, Gregorio Favale, Annabella Di Mauro, Danila La Gioia, Valentina Golino, Eduardo Sommella, Pietro Campiglia, Renato Franco, Fortunato Ciardiello, Ferdinando De Vita, Vincenzo Carafa, Lucia Altucci, Rosaria Benedetti","doi":"10.1038/s41392-025-02546-8","DOIUrl":"10.1038/s41392-025-02546-8","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma is traditionally characterized as a glycolytic tumor. However, the extent and clinical relevance of its metabolic heterogeneity remain poorly understood. In this study, we investigated whether glycolytic activity follows a consistent expression pattern across pancreatic ductal adenocarcinoma patients and explored how metabolic diversity influences therapeutic responses. Using spatial transcriptomics of ex vivo primary human pancreatic ductal adenocarcinoma specimens, along with single-cell and bulk RNA sequencing, we mapped glycolytic heterogeneity within the tumor microenvironment. Patient-derived cell models representing distinct glycolytic phenotypes were employed to assess metabolic profiles and responses to glycolytic pathway inhibition. A multiomics approach-including metabolomics, proteomics, and lipidomics-was integrated through a robust bioinformatics pipeline to identify pathway-specific variations. Our findings revealed pronounced glycolytic heterogeneity across pancreatic ductal adenocarcinoma tumors, with distinct transcriptional profiles that maintained cellular identity and spatial architecture. These glycolytic patterns are associated with clinical outcomes, suggesting their potential as prognostic indicators. Functional studies confirmed differential sensitivity to metabolic inhibitors in organoids and demonstrated their safety across models, supporting the therapeutic relevance of glycolytic stratification. Overall, this study reveals clinically significant metabolic heterogeneity in pancreatic ductal adenocarcinoma and proposes a glycolysis-based framework for patient stratification, which could guide personalized metabolic therapies and advance precision oncology in pancreatic cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"25"},"PeriodicalIF":52.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12816621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003951","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}
Pub Date : 2026-01-19DOI: 10.1038/s41392-025-02401-w
Lijun Zhao,Jiamin Yuan,Qing Yang,Jing Ma,Fenghao Yang,Yutong Zou,Ke Liu,Fang Liu
Diabetic complications represent a formidable clinical challenge characterized by hyperglycemia-induced multiorgan dysfunction and dysregulated intercellular signaling networks. Advances in spatial multiomics and single-cell transcriptomic techniques, along with insights into aberrant signaling via myokines, cytokines, hormones, the gut microbiota, and exosomes, have revealed the molecular heterogeneity and dynamic inter-organ crosstalk underlying diabetes. Digital diabetes prevention programs have demonstrated effectiveness in high-risk populations through the use of remote tools to support lifestyle changes, reduce hemoglobin A1c, and delay the onset of type 2 diabetes. The therapeutic landscape for diabetic complications has been reshaped by agents with proven cardiorenal benefits, including sodium‒glucose cotransporter 2 inhibitors, glucagon‒like peptide-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, with combination therapies offering potential additive or synergistic effects. However, their optimal application requires careful benefit-risk assessment across diverse patient populations. Novel therapeutic strategies involving mesenchymal stem cells and their derived exosomes, gut microbiota modulation, bioactive compounds from traditional Chinese medicine, and AI-assisted disease management systems offer promising approaches to correct molecular dysfunctions. This review summarizes recent advances in the mechanisms, prevention, and treatment of diabetic complications, alongside a critical examination of current bottlenecks in translational applications. The remaining challenges include establishing long-term safe regenerative therapies and effectively integrating AI into clinical workflows. Although AI shows promise, issues such as limited data diversity and low model interpretability hinder its generalizability and clinical trust. Addressing these challenges will be essential for transitioning toward a proactive, personalized, and patient-centered model of care.
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