Nature Medicine最新文献

{"title":"Immunotherapy and senolytics in head and neck squamous cell carcinoma: phase 2 trial results","authors":"Niu Liu, Jiaying Wu, Enze Deng, Jianglong Zhong, Bin Wei, Tingting Cai, Zhijun Xie, Xiaohui Duan, Sha Fu, David O. Osei-Hwedieh, Kezhi Huang, Peilin Zhuang, Ou Sha, Yunsheng Chen, Xiaobin Lv, Yingying Zhu, Lizao Zhang, Hsinyu Lin, Qunxing Li, Peichia Lu, Jiahao Miao, Teppei Yamada, Lei Cai, Hongwei Du, Sylvan C. Baca, Qingpei Huang, Soldano Ferrone, Xinhui Wang, Fang Xu, Xiaoying Fan, Song Fan","doi":"10.1038/s41591-025-03873-7","DOIUrl":"10.1038/s41591-025-03873-7","url":null,"abstract":"Recent advancements in cancer immunotherapy have improved patient outcomes, yet responses to immunotherapy remain moderate. Immunosenescence has been shown to contribute to the development and progression of various diseases; however, its specific role in solid tumors has not been fully delineated. Here we conducted a phase 2 clinical trial involving 51 patients with cancer undergoing neoadjuvant chemoimmunotherapy and applied single-cell RNA as well as TCR and BCR sequencing on tumor and blood samples to elucidate the immune cell perturbations. Our findings associate poor response with reduced levels of CCR7+ CD4+ naive T cells and CD27+ memory B cells, as well as higher expression of immunosenescence-related genes in T and B cell subsets. Using naturally aged mice and Ercc1-deficient mice (premature aging), we found that senolytics enhance the therapeutic efficacy of immunotherapy in multiple solid tumors by mitigating immunosenescence. Notably, we launched a phase 2 clinical trial (COIS-01) investigating the combination of senolytics with anti-PD-1 therapy. The results showed that the combination therapy achieved a 33.3% (95% confidence interval 16.6–54.7%) major pathological response rate with a low incidence of grade 3–4 adverse events (4.2%). These findings underscore the pivotal role of immunosenescence characteristics in influencing the effectiveness of immunotherapy and suggest a promising therapeutic efficacy along with a favorable safety for the combination of senolytics with anti-PD-1 therapy. ClinicalTrials.gov Identifier: OOC-001( NCT04718415 ) and COIS-01( NCT05724329 ). Two phase 2 trials, along with translational analysis of prospective cohorts and experimental analysis, indicate that immunosenescence as a mechanism of resistance to immunotherapy can be overcome with the senolytics dasatinib and quercetin in patients with head and neck squamous cell carcinoma.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"3047-3061"},"PeriodicalIF":50.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901594","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":"Patient-reported outcome measures add value as clinical trial endpoints","authors":"Norah L. Crossnohere, Anne L. R. Schuster, Jeffrey Bruckel, Ronald C. Chen, Amy M. Cizik, Samantha Cruz Rivera, Christopher Muth, Linda Nelsen, Derek Kyte, Albert W. Wu, Elissa Thorner, Claire Snyder, Michael Brundage","doi":"10.1038/s41591-025-03906-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03906-1","url":null,"abstract":"Asking patients about their symptoms, functioning and well-being during clinical trials can influence trial outcomes, regulatory decisions and clinical practice.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901726","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":"Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function","authors":"Yuxi Liu, Xiao Gu, Yanping Li, Fenglei Wang, Chirag M. Vyas, Cheng Peng, Danyue Dong, Yuhan Li, Yu Zhang, Yin Zhang, Oana A. Zeleznik, Jae H. Kang, Molin Wang, Frank B. Hu, Walter C. Willett, Olivia I. Okereke, A. Heather Eliassen, Peter Kraft, Meir J. Stampfer, Dong D. Wang","doi":"10.1038/s41591-025-03891-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03891-5","url":null,"abstract":"<p>Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) have a substantial genetic basis, with <i>APOE4</i> homozygotes increasingly recognized as a distinct genetic subtype. To identify genotype-specific metabolic pathways and modifiable risk factors, we integrated genetic, plasma metabolomic and dietary data from 4,215 women and 1,490 men in prospective cohorts. Here we show that the associations of 57 metabolites with dementia risk varied by <i>APOE4</i> genotype or other AD/ADRD risk variants. For example, cholesteryl esters and sphingomyelins were most strongly associated with increased dementia risk in <i>APOE4</i> homozygotes, whereas inverse associations with glycerides were specific to this genotype. Dimethylguanidino-valeric acid was more strongly associated with dementia risk among carriers of the rs2154481-C allele (<i>APP</i>). Adherence to the Mediterranean diet more effectively modulated dementia-related metabolites in <i>APOE4</i> homozygotes, suggesting targeted prevention strategies. Incorporating metabolomic data modestly improved dementia risk prediction, particularly during early follow-up. Mendelian randomization analysis identified 19 putative causal relationships between metabolites and cognitive outcomes, including protective effects of 4-guanidinobutanoate, carotenoids and <i>N</i>⁶-carbamoylthreonyladenosine. These findings reveal genotype-dependent metabolic profiles of cognitive health and support precision nutrition approaches for ADRD prevention.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"9 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901593","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":"Pig-to-human lung xenotransplantation into a brain-dead recipient","authors":"Jianxing He, Jiang Shi, Chao Yang, Guilin Peng, Chunrong Ju, Yi Zhao, Hui Liu, Ping He, Xiaoqing Liu, Zuopeng Zhang, Chuanbao Chen, Dengke Pan, Zifeng Yang, Wenda Guang, Hongtao Li, Zhonghua Chen, Menyang Liu, Hengrui Liang, Weiqing Huang, Kyeongman Jeon, Toyofumi F. Chen-Yoshikawa, A. Justin Rucker, Amos Lal, Nanshan Zhong, Kang Zhang, Xiaoyou Liu, Xin Xu","doi":"10.1038/s41591-025-03861-x","DOIUrl":"https://doi.org/10.1038/s41591-025-03861-x","url":null,"abstract":"<p>Genetically engineered pig lungs have not previously been transplanted into humans, leaving key questions unanswered regarding the human immune response in the context of a xenotransplanted lung and the possibility of hyperacute rejection. Here, we report a case of pig-to-human lung xenotransplantation, in which a lung from a six-gene-edited pig was transplanted into a 39-year-old brain-dead male human recipient following a brain hemorrhage. The lung xenograft maintained viability and functionality over the course of the 216 hours of the monitoring period, without signs of hyperacute rejection or infection. Severe edema resembling primary graft dysfunction was observed at 24 hours after transplantation, potentially due to ischemia–reperfusion injury. Antibody-mediated rejection appeared to contribute to xenograft damage on postoperative days 3 and 6, with partial recovery by day 9. Immunosuppression included rabbit anti-thymocyte globulin, basiliximab, rituximab, eculizumab, tofacitinib, tacrolimus, mycophenolate mofetil and tapering steroids, with adjustments made during the postoperative period based on assessments of immune status. Although this study demonstrates the feasibility of pig-to-human lung xenotransplantation, substantial challenges relating to organ rejection and infection remain, and further preclinical studies are necessary before clinical translation of this procedure.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"17 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901724","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":"The need for molecular tumor boards","authors":"Funda Meric-Bernstam","doi":"10.1038/s41591-025-03892-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03892-4","url":null,"abstract":"Genomic sequencing promises targeted treatment for every patient with cancer; the reality is much tougher to deliver.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901725","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":"Ultra-processed diets promote excess calorie consumption","authors":"Marion Nestle","doi":"10.1038/s41591-025-03910-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03910-5","url":null,"abstract":"A clinical trial designed to overcome limitations of previous trials now confirms that individuals consume more calories from ultra-processed diets than from minimally processed diets, even when both diets meet UK dietary guidelines and participants are losing weight.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"17 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901604","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":"Overcoming zero-sum thinking to advance US population health","authors":"Vincent Guilamo-Ramos, Marco Thimm-Kaiser, Adam Benzekri, Daniel E. Dawes","doi":"10.1038/s41591-025-03907-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03907-0","url":null,"abstract":"<p>There is broad consensus that the US healthcare system is failing. Policy initiatives to reduce costs and improve healthcare outcomes have been longstanding priorities across presidential administrations, but there has been limited success. The USA continues to achieve worse outcomes than those of comparable high-income countries while spending more on healthcare¹.</p><p>One important factor preventing reforms is zero-sum thinking about health inequities: the belief that investing to improve the health of population segments with the worst outcomes comes at the expense of those with better baseline health². Here we challenge the zero-sum thinking that denies the broader, population-level benefits of eliminating health inequities. First, we show how health inequities harm the whole US population, not just marginalized groups, highlighting how reducing inequities benefits everyone. Second, we identify four common fallacies in healthcare-related zero-sum thinking and counter each. Finally, we argue the importance of overcoming zero-sum thinking for advancing substantive healthcare reforms.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"9 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901612","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":"Concern for the validity of short-term dietary crossover trials","authors":"David S. Ludwig,&nbsp;Walter C. Willett,&nbsp;Mary E. Putt","doi":"10.1038/s41591-025-03909-y","DOIUrl":"10.1038/s41591-025-03909-y","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"2913-2914"},"PeriodicalIF":50.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901613","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":"Reply to: Concern for the validity of short-term dietary crossover trials","authors":"Kevin D. Hall","doi":"10.1038/s41591-025-03911-4","DOIUrl":"10.1038/s41591-025-03911-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 9","pages":"2915-2916"},"PeriodicalIF":50.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901606","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":"GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/phase 2 trial","authors":"Franco Locatelli, Daria Pagliara, Maria A. De Ioris, Marco Becilli, Giada Del Baldo, Annalisa Serra, Angela Mastronuzzi, Maria G. Cefalo, Giuseppina Li Pira, Giovanna Leone, Valentina Bertaina, Francesco Fabozzi, Matteo Di Nardo, Chiara Rosignoli, Maria Luisa D’Andrea, Alessandro Crocoli, Sabina Vennarini, Matilde Sinibaldi, Stefano Di Cecca, Marika Guercio, Laura Iaffaldano, Barbarella Lucarelli, Mattia Algeri, Pietro Merli, Giovanna S. Colafati, Biagio De Angelis, Concetta Quintarelli, Francesca del Bufalo","doi":"10.1038/s41591-025-03874-6","DOIUrl":"https://doi.org/10.1038/s41591-025-03874-6","url":null,"abstract":"<p>Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2–CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/phase 2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2–CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 × 10⁶CAR⁺ cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32—excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2–CART01 persisted ≥12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 × 10⁶ GD2–CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 78% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after ≥3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2–CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier: NCT03373097.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"18 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901620","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}