Cell Reports MedicinePub Date : 2025-03-18Epub Date: 2025-03-07DOI: 10.1016/j.xcrm.2025.101998
Pengyu Zong, Cindy Li, Jianlin Feng, Zhichao Yue, Nicholas Legere, Albert S Yu, Fahad Shah, Adrianna Perez, Zhu Li, Evan Jellison, Yasuo Mori, Barbara Miller, Rajkumar Verma, Bruce Liang, Lixia Yue
{"title":"TRPM2 overactivation drives hyperlipidemia-induced dysfunction of myeloid cells and neurovascular units.","authors":"Pengyu Zong, Cindy Li, Jianlin Feng, Zhichao Yue, Nicholas Legere, Albert S Yu, Fahad Shah, Adrianna Perez, Zhu Li, Evan Jellison, Yasuo Mori, Barbara Miller, Rajkumar Verma, Bruce Liang, Lixia Yue","doi":"10.1016/j.xcrm.2025.101998","DOIUrl":"10.1016/j.xcrm.2025.101998","url":null,"abstract":"<p><p>Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe<sup>-/-</sup> mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2's pivotal role in mediating hyperlipidemia's detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyperlipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101998"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584195","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 : 2025-03-18Epub Date: 2025-03-07DOI: 10.1016/j.xcrm.2025.102001
Caleb Mayer, Olivia Walch, Walter Dempsey, Kevin Hannay, Caroline Clingan, Zoe Bowen, Michelle Rozwadowski, Zachery R Reichert, N Lynn Henry, Joshi J Alumkal, Muneesh Tewari, Daniel B Forger, Sung Won Choi
{"title":"A circadian and app-based personalized lighting intervention for the reduction of cancer-related fatigue.","authors":"Caleb Mayer, Olivia Walch, Walter Dempsey, Kevin Hannay, Caroline Clingan, Zoe Bowen, Michelle Rozwadowski, Zachery R Reichert, N Lynn Henry, Joshi J Alumkal, Muneesh Tewari, Daniel B Forger, Sung Won Choi","doi":"10.1016/j.xcrm.2025.102001","DOIUrl":"10.1016/j.xcrm.2025.102001","url":null,"abstract":"<p><p>Lighting interventions can mitigate fatigue by promoting circadian rhythmicity. We test whether individualized, wearable-based lighting interventions delivered via a mobile app reduce cancer-related fatigue in a randomized controlled trial with 138 breast cancer, prostate cancer, and hematopoietic stem cell transplant patients. Participants are randomized to tailored lighting intervention or control. The primary endpoint is PROMIS fatigue 4a at trial end, with secondary endpoints including change in daily fatigue, sleep, anxiety, depression, physical function, and overall health. Fatigue T-scores at week 11 do not differ between groups but decrease significantly from week 1 to week 11 (3.07 points, p = 0.001) in the intervention group, with a significant final-week treatment effect (p = 0.014). Daily fatigue, anxiety, sleep disturbance, and physical function improve within intervention. Further studies are needed to see if these results generalize in broader cancer care. The trial is registered at ClinicalTrials.gov (trial registration number: NCT04827446).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102001"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584932","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":"Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.","authors":"Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad","doi":"10.1016/j.xcrm.2025.102021","DOIUrl":"10.1016/j.xcrm.2025.102021","url":null,"abstract":"<p><p>Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8<sup>+</sup> T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102021"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662628","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":"Pharmacological rescue of mutant p53 triggers spontaneous tumor regression via immune responses.","authors":"Jiabing Li, Shuang Zhang, Baohui Wang, Yuting Dai, Jiale Wu, Dianjia Liu, Ying Liang, Shujun Xiao, Zhengyuan Wang, Jiaqi Wu, Derun Zheng, Xueqin Chen, Fangfang Shi, Kai Tan, Xianting Ding, Huaxin Song, Sujiang Zhang, Min Lu","doi":"10.1016/j.xcrm.2025.101976","DOIUrl":"10.1016/j.xcrm.2025.101976","url":null,"abstract":"<p><p>Tumor suppressor p53 is the most frequently mutated protein in cancer, possessing untapped immune-modulating capabilities in anticancer treatment. Here, we investigate the efficacy and underlying mechanisms of pharmacological reactivation of mutant p53 in treating spontaneous tumors in mice. In the p53 R279W (equivalent to the human hotspot R282W) mouse model developing spontaneous tumors, arsenic trioxide (ATO) treatment through drinking water significantly prolongs the survival of mice, dependent on p53-R279W reactivation. Transient regressions of spontaneous T-lymphomas are observed in 70% of the ATO-treated mice, accompanied by interferon (IFN) response. In allograft models, the tumor-suppressive effect of reactivated p53-R279W is detectably reduced in both immunodeficient Rag1<sup>-/-</sup> and CD8<sup>+</sup> T cell-depleted mice. ATO also activates the IFN pathway in human cancer cells harboring various p53 mutations, as well as in primary samples derived from the p53-mutant patient treated with ATO. Together, p53 could serve as an alternative therapeutic target for the development of immunotherapies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101976"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476457","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}
Diwei Zheng, Le Qin, Jiang Lv, Meihui Che, Bingjia He, Yongfang Zheng, Shouheng Lin, Yuekun Qi, Ming Li, Zhaoyang Tang, Bin-Chao Wang, Yi-Long Wu, Robert Weinkove, Georgia Carson, Yao Yao, Nathalie Wong, James Lau, Jean Paul Thiery, Dajiang Qin, Bin Pan, Kailin Xu, Zhenfeng Zhang, Peng Li
{"title":"CD4<sup>+</sup> anti-TGF-β CAR T cells and CD8<sup>+</sup> conventional CAR T cells exhibit synergistic antitumor effects.","authors":"Diwei Zheng, Le Qin, Jiang Lv, Meihui Che, Bingjia He, Yongfang Zheng, Shouheng Lin, Yuekun Qi, Ming Li, Zhaoyang Tang, Bin-Chao Wang, Yi-Long Wu, Robert Weinkove, Georgia Carson, Yao Yao, Nathalie Wong, James Lau, Jean Paul Thiery, Dajiang Qin, Bin Pan, Kailin Xu, Zhenfeng Zhang, Peng Li","doi":"10.1016/j.xcrm.2025.102020","DOIUrl":"10.1016/j.xcrm.2025.102020","url":null,"abstract":"<p><p>Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4<sup>+</sup> T cells. Here, we demonstrate that CD4<sup>+</sup> but not CD8<sup>+</sup> anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4<sup>+</sup> T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8<sup>+</sup> T cells in vivo. Tumor-infiltrating CD4<sup>+</sup> T28zT2 T cells are enriched with TCF-1<sup>+</sup>IL7R<sup>+</sup> memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4<sup>+</sup> T28zT2 T cells and CD8<sup>+</sup> anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4<sup>+</sup> T cells is a promising strategy for eradicating solid tumors.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102020"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662629","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}
Hamed Moheimani, Xuejing Sun, Mehves Ozel, Jennifer L Darby, Erika P Ong, Tunde Oyebamiji, Upendra K Kar, Mark H Yazer, Matthew D Neal, Francis X Guyette, Stephen R Wisniewski, Bryan A Cotton, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Christopher D Barrett, Jishnu Das, Jason L Sperry, Timothy R Billiar
{"title":"High-dimensional analysis of injured patients reveals distinct circulating proteomic profiles in plasma vs. whole blood resuscitation.","authors":"Hamed Moheimani, Xuejing Sun, Mehves Ozel, Jennifer L Darby, Erika P Ong, Tunde Oyebamiji, Upendra K Kar, Mark H Yazer, Matthew D Neal, Francis X Guyette, Stephen R Wisniewski, Bryan A Cotton, Jeremy W Cannon, Martin A Schreiber, Ernest E Moore, Nicholas Namias, Joseph P Minei, Christopher D Barrett, Jishnu Das, Jason L Sperry, Timothy R Billiar","doi":"10.1016/j.xcrm.2025.102022","DOIUrl":"10.1016/j.xcrm.2025.102022","url":null,"abstract":"<p><p>Early blood product resuscitation is often essential for optimal trauma care. However, the effects of different products on the underlying trauma-induced coagulopathy and immune dysfunction are not well described. Here, we use high-dimensional analysis and causal modeling in a longitudinal study to explore the circulating proteomic response to plasma as a distinct component versus low-titer O whole blood (LTOWB), which contains plasma. We highlight the differential impacts of plasma and LTOWB on immune mediator levels and the distinct capacity of plasma to modulate coagulation by elevating fibrinogen and factor XIII and reducing platelet factor 4. A higher proportion of plasma in prehospital resuscitation is associated with improved admission time coagulation parameters in patients with severe shock and elevated brain injury markers and reduced post-admission transfusion volumes in those suffering from traumatic brain injury (TBI) and blunt injury. While LTOWB offers broad hemostatic benefits, our findings demonstrate specific advantages of plasma and support individualized transfusion strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102022"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662630","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}
Tine J Monberg, Santeri A Pakola, Benedetta Albieri, Eva Ellebaek, Marco Donia, Rikke L Eefsen, Troels H Borch, Tatiana V Kudling, Torben Lorentzen, Helle W Hendel, Cecilie Vestergaard, Cathrine Lorentzen, Rikke B Holmstroem, Victor Arias, Amir Khammari, Claudia Kistler, João M Santos, James H A Clubb, Lyna Haybout, Marie C W Westergaard, Özcan Met, Dafne C A Quixabeira, Elise Jirovec, Riikka Havunen, Suvi Sorsa, Victor Cervera-Carrascon, Brigitte Dreno, Akseli Hemminki, Inge Marie Svane
{"title":"Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma.","authors":"Tine J Monberg, Santeri A Pakola, Benedetta Albieri, Eva Ellebaek, Marco Donia, Rikke L Eefsen, Troels H Borch, Tatiana V Kudling, Torben Lorentzen, Helle W Hendel, Cecilie Vestergaard, Cathrine Lorentzen, Rikke B Holmstroem, Victor Arias, Amir Khammari, Claudia Kistler, João M Santos, James H A Clubb, Lyna Haybout, Marie C W Westergaard, Özcan Met, Dafne C A Quixabeira, Elise Jirovec, Riikka Havunen, Suvi Sorsa, Victor Cervera-Carrascon, Brigitte Dreno, Akseli Hemminki, Inge Marie Svane","doi":"10.1016/j.xcrm.2025.102016","DOIUrl":"10.1016/j.xcrm.2025.102016","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocytes (TILs) are effective in the treatment of metastatic melanoma (MM), but toxicity limits its application. TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus producing interleukin-2 (IL-2) and tumor necrosis factor (TNF) upon replication. In this phase 1 trial, 17 patients with metastatic checkpoint inhibitor-resistant melanoma are treated with TILT-123 and TILs without preconditioning chemotherapy or postconditioning IL-2. The treatment is safe and feasible. According to computed tomography (CT), the objective response rate is 11.7% (2/17) and disease control is observed in 35% (6/17), including a partial response lasting >8 months and a durable complete response in a mucosal melanoma patient. According to positron emission tomography (PET), disease control is observed in 7/15 (47%) with minor or partial responses in 4/15 (27%). In the initial TILT-123 monotherapy phase of the trial, disease control is observed in 6/17 (35%) and 10/16 (63%) in CT and PET, respectively. The study demonstrates good tolerability and preliminary efficacy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102016"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662636","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":"The IFN-high phenotype: A biomarker-driven breakthrough in colorectal cancer treatment.","authors":"Lize Allonsius, Luca Kelecom, Damya Laoui","doi":"10.1016/j.xcrm.2025.102025","DOIUrl":"10.1016/j.xcrm.2025.102025","url":null,"abstract":"<p><p>Patient stratification is crucial for improving immunotherapy effectiveness. Acha-Sagredo et al. identified an interferon (IFN)-high immunophenotype and CD74 overexpression as predictors for immunotherapy response in colorectal cancer (CRC). This signature, involving cytotoxic T cells and antigen-presenting macrophages, was found in both mismatch repair-deficient and -proficient CRCs. CD74 overexpression could serve as a biomarker, enabling personalized CRC treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 3","pages":"102025"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662643","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 : 2025-03-18Epub Date: 2025-03-07DOI: 10.1016/j.xcrm.2025.102000
Shuai Yang, Xinyao Qiu, Yingcheng Yang, Jing Wu, Shan Wang, Bo Zheng, Jianmin Wu, Tao Zhou, Yangqianwen Zhang, Mixue Bai, Shuowu Liu, Zihan Zhao, Yani Zhang, Yixian Wang, Jinxia Bao, Mengye Wu, Dongdong Xue, Meiyu Bao, Ji Hu, Siyun Shen, Hongyang Wang, Lei Chen
{"title":"LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis.","authors":"Shuai Yang, Xinyao Qiu, Yingcheng Yang, Jing Wu, Shan Wang, Bo Zheng, Jianmin Wu, Tao Zhou, Yangqianwen Zhang, Mixue Bai, Shuowu Liu, Zihan Zhao, Yani Zhang, Yixian Wang, Jinxia Bao, Mengye Wu, Dongdong Xue, Meiyu Bao, Ji Hu, Siyun Shen, Hongyang Wang, Lei Chen","doi":"10.1016/j.xcrm.2025.102000","DOIUrl":"10.1016/j.xcrm.2025.102000","url":null,"abstract":"<p><p>Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206<sup>+</sup> macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102000"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582219","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":"Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma.","authors":"Haoran Mu, Qi Zhang, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Liu Yang, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua","doi":"10.1016/j.xcrm.2025.101977","DOIUrl":"10.1016/j.xcrm.2025.101977","url":null,"abstract":"<p><p>Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a \"cold\" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (PD-L1) transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8<sup>+</sup> T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101977"},"PeriodicalIF":11.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472354","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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