{"title":"Targeting USP21 to inhibit abdominal aortic aneurysm progression by suppressing the phenotypic transition of vascular smooth muscle cells.","authors":"Huidan Zhang, Hongwei Yue, Yijun Sun, Guangqi Sun, Kehui Yang, Tangxing Jiang, Sumei Cui, Yang Liu, Yunyun Guo, Wencheng Zhang, Cheng Zhang, Yuguo Chen, Feng Xu","doi":"10.1016/j.xcrm.2025.102328","DOIUrl":"10.1016/j.xcrm.2025.102328","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a life-threatening condition lacking effective treatment. We investigate the role of the deubiquitinating enzyme USP21 in AAA development. Proteomic analysis reveals significant upregulation of USP21 in murine and human abdominal aortic tissues. Using USP21 global knockout models induced by angiotensin II or porcine pancreatic elastase (PPE), and vascular smooth muscle cell (VSMC)-specific models, we assess USP21's impact on AAA. Coimmunoprecipitation and mass spectrometry identify downstream targets of USP21. USP21 exacerbates AAA by stabilizing aldehyde dehydrogenase 2 (ALDH2) and promoting VSMC dedifferentiation and phenotypic changes. Pharmacological inhibition of USP21 with disulfiram shows therapeutic potential against AAA progression, with efficacy reduced in ALDH2<sup>E506K</sup> mutant mice. Our findings highlight USP21 as a critical regulator in AAA pathogenesis and a potential therapeutic target.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102328"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029006","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 : 2025-09-16Epub Date: 2025-09-08DOI: 10.1016/j.xcrm.2025.102350
Rafaela Abrantes, Christopher Forcados, David J Warren, Liliana Santos-Ferreira, Karianne Giller Fleten, Emanuel Senra, Ana Filipa Costa, Klara Krpina, Rui Henrique, Ann Magritt Liberg, Puneet Rawat, Pascal Gelebart, Emmet McCormack, Line Bjørge, Ben Davidson, Victor Greiff, Daniela Elena Costea, Filipe Pinto, Kjersti Flatmark, Catarina Gomes, Else Marit Inderberg, Celso A Reis, Sébastien Wälchli
{"title":"Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors.","authors":"Rafaela Abrantes, Christopher Forcados, David J Warren, Liliana Santos-Ferreira, Karianne Giller Fleten, Emanuel Senra, Ana Filipa Costa, Klara Krpina, Rui Henrique, Ann Magritt Liberg, Puneet Rawat, Pascal Gelebart, Emmet McCormack, Line Bjørge, Ben Davidson, Victor Greiff, Daniela Elena Costea, Filipe Pinto, Kjersti Flatmark, Catarina Gomes, Else Marit Inderberg, Celso A Reis, Sébastien Wälchli","doi":"10.1016/j.xcrm.2025.102350","DOIUrl":"10.1016/j.xcrm.2025.102350","url":null,"abstract":"<p><p>Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102350"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029067","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 : 2025-09-16Epub Date: 2025-08-08DOI: 10.1016/j.xcrm.2025.102264
Luke Spray, Gavin Richardson, Judith Haendeler, Joachim Altschmied, Valencia Rumampouw, Sienna B Wallis, Georgios Georgiopoulos, Stephen White, Amanda Unsworth, Konstantinos Stellos, Simon Tual-Chalot, Ioakim Spyridopoulos
{"title":"Cardiovascular inflammaging: Mechanisms, consequences, and therapeutic perspectives.","authors":"Luke Spray, Gavin Richardson, Judith Haendeler, Joachim Altschmied, Valencia Rumampouw, Sienna B Wallis, Georgios Georgiopoulos, Stephen White, Amanda Unsworth, Konstantinos Stellos, Simon Tual-Chalot, Ioakim Spyridopoulos","doi":"10.1016/j.xcrm.2025.102264","DOIUrl":"10.1016/j.xcrm.2025.102264","url":null,"abstract":"<p><p>Both aging and systemic inflammation are major risk factors for cardiovascular disease. This review summarizes the interrelationship of aging and inflammation-known as inflammaging-and the consequences for cardiovascular health. We discuss mechanisms including epigenetic modification, mitochondrial dysfunction, cellular senescence, and gut dysbiosis, many of which are themselves interrelated. Increasing understanding of inflammaging provides an array of biomarkers, some of which are now recommended in international guidelines. We also discuss therapeutic strategies aiming to modify the process of inflammaging and improve cardiovascular disease outcomes, either with immunomodulating agents or with therapies targeted at specific mechanisms, such as senolytics, telomerase activators, and pre- and probiotic supplementation. We conclude that inflammaging is a key part of cardiovascular aging and provides encouraging opportunities for new therapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102264"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811853","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":"Psychedelics for major depression-From controlled research settings into broader clinical use.","authors":"Mihai Avram, Stefan Borgwardt","doi":"10.1016/j.xcrm.2025.102361","DOIUrl":"10.1016/j.xcrm.2025.102361","url":null,"abstract":"<p><p>Psychedelics have shown promising antidepressant effects in recent phase 2 randomized controlled trials, with phase 3 studies underway. While therapeutic outcomes are encouraging, the underlying mechanisms-from receptor-level pharmacology to subjective experience and context-remain only partially understood. We highlight clinical and mechanistic advances and outline priorities for future research.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 9","pages":"102361"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079714","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":"High-dose ascorbic acid selectively induces pyroptosis in LKB1-deficient lung cancer and sensitizes immunotherapy.","authors":"Xiangyu Sun, Xiaoting Cai, Shangbiao Li, Ruozheng Pi, Zeqin Guo, Jiayu Jiang, Pinhao Wang, Jingrong Xiong, Zhuangzhuang Liu, Zixuan Rong, Zihang Yu, Xiaonan Zhang, Jiaqi Chen, Duanduan Han, Yanpei Zhang, Jiale Tan, Yan Lin, Zhuocheng Zou, Haochen Ai, Fangfang Kang, Xuejun Guo, Zhongyi Dong, Dehua Wu, Xue Bai","doi":"10.1016/j.xcrm.2025.102291","DOIUrl":"10.1016/j.xcrm.2025.102291","url":null,"abstract":"<p><p>Liver kinase B1 (LKB1)-deficient non-small cell lung cancers (NSCLCs) exhibit primary resistance to immune checkpoint inhibitors (ICIs). The redox imbalance inherent in these tumors may represent a potential therapeutic vulnerability. High-dose ascorbic acid (AA) could induce cell redox imbalance. Here, we uncover that LKB1 deficiency upregulates the transporter GLUT1, which enables the accumulation of AA, thereby exacerbating redox imbalance in NSCLC cells. This triggers pyroptosis in LKB1-deficient NSCLC cells via the H<sub>2</sub>O<sub>2</sub>/reactive oxygen species (ROS)-caspase-3-gasdermin-E (GSDME) axis. In pre-clinical models, high-dose AA reverses ICI resistance and remodels the immune microenvironment, characterized by T cell factor 1 (TCF1)<sup>+</sup>CD8<sup>+</sup> T cell (progenitor-exhausted CD8<sup>+</sup> T cell [Tpex]) infiltration. Pyroptosis-driven immunogenic cell death (ICD) promotes cross-presenting dendritic cell (DC) maturation, which drives Tpex proliferation. Crucially, in Batf3<sup>-/-</sup> mice lacking functional CD103<sup>+</sup> DC populations, both Tpex expansion and therapeutic benefits are abrogated, confirming DC dependence. In addition, GSDME is validated as a gatekeeper of pyroptosis-driven antitumor immunity. This work provides a rationale for clinical trials combining ICI with high-dose AA.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102291"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862154","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 : 2025-09-16Epub Date: 2025-08-18DOI: 10.1016/j.xcrm.2025.102301
M Angela Aznar, Charly R Good, Julie S Barber-Rotenberg, Sangya Agarwal, Wesley Wilson, Alex Watts, Zhen Zhang, Donna Gonzales, Greg Donahue, Wei-Ting Hwang, Austin K Rennels, Andrew J Rech, Shunichiro Kuramitsu, Hua Huang, Karl M Glastad, Katherine A Alexander, Gabriela Plesa, Emily Dowd, Andrea Brennan, Donald L Siegel, Janos Tanyi, Andrew Haas, Drew A Torigian, Gregory Nadolski, Vanessa E Gonzalez, Elizabeth O Hexner, Joseph A Fraietta, Julie K Jadlowsky, Regina M Young, Shelley L Berger, Carl H June, Mark H O'Hara
{"title":"Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer.","authors":"M Angela Aznar, Charly R Good, Julie S Barber-Rotenberg, Sangya Agarwal, Wesley Wilson, Alex Watts, Zhen Zhang, Donna Gonzales, Greg Donahue, Wei-Ting Hwang, Austin K Rennels, Andrew J Rech, Shunichiro Kuramitsu, Hua Huang, Karl M Glastad, Katherine A Alexander, Gabriela Plesa, Emily Dowd, Andrea Brennan, Donald L Siegel, Janos Tanyi, Andrew Haas, Drew A Torigian, Gregory Nadolski, Vanessa E Gonzalez, Elizabeth O Hexner, Joseph A Fraietta, Julie K Jadlowsky, Regina M Young, Shelley L Berger, Carl H June, Mark H O'Hara","doi":"10.1016/j.xcrm.2025.102301","DOIUrl":"10.1016/j.xcrm.2025.102301","url":null,"abstract":"<p><p>Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK<sup>+</sup> phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, though with donor-dependent variability. However, single-knockout cells eventually fail. Conversely, ID3 and SOX4 double-knockout CAR T cells exhibit prolonged relapse-free survival, demonstrating a sustained therapeutic effect and a potential avenue for engineering more potent CAR T cells in PDAC. This study was registered at ClinicalTrials.gov (NCT03323944).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102301"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882306","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 : 2025-09-16Epub Date: 2025-08-29DOI: 10.1016/j.xcrm.2025.102316
Daria Afenteva, Rong Yu, Anna Rajavuori, Marina Salvadores, Inga-Maria Launonen, Kari Lavikka, Kaiyang Zhang, Anna Pirttikoski, Giovanni Marchi, Sanaz Jamalzadeh, Veli-Matti Isoviita, Yilin Li, Giulia Micoli, Erdogan Pekcan Erkan, Matias M Falco, Daniela Ungureanu, Alexandra Lahtinen, Jaana Oikkonen, Sakari Hietanen, Anna Vähärautio, Inderpreet Sur, Anni Virtanen, Anniina Färkkilä, Johanna Hynninen, Taru A Muranen, Jussi Taipale, Sampsa Hautaniemi
{"title":"Multi-omics analysis reveals the attenuation of the interferon pathway as a driver of chemo-refractory ovarian cancer.","authors":"Daria Afenteva, Rong Yu, Anna Rajavuori, Marina Salvadores, Inga-Maria Launonen, Kari Lavikka, Kaiyang Zhang, Anna Pirttikoski, Giovanni Marchi, Sanaz Jamalzadeh, Veli-Matti Isoviita, Yilin Li, Giulia Micoli, Erdogan Pekcan Erkan, Matias M Falco, Daniela Ungureanu, Alexandra Lahtinen, Jaana Oikkonen, Sakari Hietanen, Anna Vähärautio, Inderpreet Sur, Anni Virtanen, Anniina Färkkilä, Johanna Hynninen, Taru A Muranen, Jussi Taipale, Sampsa Hautaniemi","doi":"10.1016/j.xcrm.2025.102316","DOIUrl":"10.1016/j.xcrm.2025.102316","url":null,"abstract":"<p><p>Ovarian high-grade serous carcinoma (HGSC) is one of the deadliest gynecological malignancies, with 10%-15% of patients exhibiting primary resistance to first-line chemotherapy. To characterize the molecular drivers of chemo-refractoriness, we perform multi-omics profiling of treatment-naive biopsies from patients with refractory HGSC enrolled in the DECIDER observational trial. We demonstrate that chemo-refractory HGSC is characterized by diminished interferon type I (IFN-I) and enhanced hypoxia pathway activity, and baseline IFN-I activity in chemo-naive cancer is an independent prognostic factor. Single-cell RNA sequencing and spatial protein profiling analyses corroborate the importance of elevated IFN-I activity in response to chemotherapy. Importantly, in vitro experiments demonstrate that high levels of IFN-I signaling increase cell chemosensitivity to platinum in a cell-autonomous manner. Together, these findings indicate that the IFN-I pathway activity in HGSC cancer cells predicts response to first-line chemotherapy in HGSC, proposing the stimulation of the IFN-I response as a therapeutic strategy. The study is registered at ClinicalTrials.gov (NCT04846933).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102316"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944781","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 : 2025-09-16Epub Date: 2025-09-03DOI: 10.1016/j.xcrm.2025.102326
You Jin Chang, Leonie K Heilbronn, Amy T Hutchison
{"title":"Established dietary interventions and time-restricted eating for cardiovascular disease prevention.","authors":"You Jin Chang, Leonie K Heilbronn, Amy T Hutchison","doi":"10.1016/j.xcrm.2025.102326","DOIUrl":"10.1016/j.xcrm.2025.102326","url":null,"abstract":"<p><p>Obesity and its associated metabolic disturbances, including insulin resistance, inflammation, hypertension, dyslipidemia, and plaque progression, are key drivers of cardiovascular risk. Established dietary strategies, such as the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), and calorie restriction (CR), play a crucial role in preventing and slowing the progression of cardiovascular diseases (CVDs). Time-restricted eating (TRE) is a form of intermittent fasting where food intake is limited to 6-10 h daily, typically during daytime hours, and is showing potential to improve cardiovascular health. This review examines the evidence for and mechanisms underlying established dietary strategies and TRE in improving cardiovascular outcomes, and it explores whether incorporating established dietary interventions alongside TRE could provide synergistic cardiovascular benefits.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102326"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999747","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 : 2025-09-16Epub Date: 2025-08-15DOI: 10.1016/j.xcrm.2025.102296
Zhenghang Wang, Xicheng Wang, Xiaoyan Zhang, Jiahua Leng, Ming Cui, Ji Zhang, Quan Wang, Yu Sun, Ting Xu, Mifen Chen, Jian Li, Lin Shen
{"title":"Toripalimab, bevacizumab, and irinotecan in dMMR/MSI locally advanced colorectal cancer: First-stage results from a phase 1b/2 trial.","authors":"Zhenghang Wang, Xicheng Wang, Xiaoyan Zhang, Jiahua Leng, Ming Cui, Ji Zhang, Quan Wang, Yu Sun, Ting Xu, Mifen Chen, Jian Li, Lin Shen","doi":"10.1016/j.xcrm.2025.102296","DOIUrl":"10.1016/j.xcrm.2025.102296","url":null,"abstract":"<p><p>This is the first stage of the phase 1b/2 trial evaluating the effectiveness and safety of toripalimab, irinotecan, and bevacizumab in patients with rectal cancer refusing up-front surgery or radiation therapy (rectum cohort) and patients with T4NanyM0 colon cancer (colon cohort) with deficiency of mismatch repair (dMMR) or microsatellite instability (MSI). This trial allows a doctor-patient shared decision-making process to determine whether to omit irinotecan or bevacizumab and the optimal surgery timing. The primary endpoint pathological complete response (pCR) rates in the full analysis set (FAS) and per-protocol set (PPS) are 57.1% (95% confidence interval [CI] 28.9-82.3) and 66.7% (34.9-90.1), respectively, in the colon cohort (n = 14) and 75.0% (35.6-95.5) and 100% (51.7-100.0), respectively, in the rectum cohort (n = 8). No disease recurrence occurs in PPS. No grade 4-5 drug-related adverse events are observed. Toripalimab with or without irinotecan and bevacizumab shows promising efficacy and manageable toxicity in dMMR/MSI T4NanyM0 colon cancer and locally advanced rectal cancer (ClinicalTrials.gov: NCT04988191).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102296"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862156","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 : 2025-09-16Epub Date: 2025-09-01DOI: 10.1016/j.xcrm.2025.102324
Freya Q Zhang, Jiacheng Li, Rukang Zhang, Jiayi Tu, Zhicheng Xie, Takemasa Tsuji, Hardik Shah, Matthew O Ross, Ruitu Lyu, Junko Matsuzaki, Anna Tabor, Kelly Xue, Fatima Choudhry, Chunzhao Yin, Hamed R Youshanlouei, Syed Shah, Michael W Drazer, Yu-Ying He, B Marc Bissonnette, Yuancheng Li, Hui Mao, Jun Huang, Lei Dong, Rui Su, Chuan He, Kunle Odunsi, Jing Chen, Hao Fan
{"title":"Zeaxanthin augments CD8<sup>+</sup> effector T cell function and immunotherapy efficacy.","authors":"Freya Q Zhang, Jiacheng Li, Rukang Zhang, Jiayi Tu, Zhicheng Xie, Takemasa Tsuji, Hardik Shah, Matthew O Ross, Ruitu Lyu, Junko Matsuzaki, Anna Tabor, Kelly Xue, Fatima Choudhry, Chunzhao Yin, Hamed R Youshanlouei, Syed Shah, Michael W Drazer, Yu-Ying He, B Marc Bissonnette, Yuancheng Li, Hui Mao, Jun Huang, Lei Dong, Rui Su, Chuan He, Kunle Odunsi, Jing Chen, Hao Fan","doi":"10.1016/j.xcrm.2025.102324","DOIUrl":"10.1016/j.xcrm.2025.102324","url":null,"abstract":"<p><p>The detailed mechanisms underlying the regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we apply a co-culture-based screening approach using a blood nutrient compound library and identify zeaxanthin (ZEA), a dietary carotenoid pigment found in many fruits and vegetables and known for its role in eye health, as an immunomodulator that enhances the cytotoxicity of CD8<sup>+</sup> T cells against tumor cells. Oral supplementation with ZEA, but not its structural isomer lutein (LUT), enhances anti-tumor immunity in vivo. Integrated multi-omics mechanistic studies reveal that ZEA promotes T cell receptor (TCR) stimulation on the CD8<sup>+</sup> T cell surface, leading to improved intracellular TCR signaling for effector T cell function. Hence, ZEA treatment augments the efficacy of anti-PD1 immune checkpoint inhibitor in vivo and the cytotoxicity of human TCR gene-engineered CD8<sup>+</sup> T cells in vitro. Our findings uncover a previously unknown immunoregulatory function of ZEA, which has translational potential as a dietary element in bolstering immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102324"},"PeriodicalIF":10.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944871","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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