Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors
Background Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.M...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010403.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841556533504114688 |
|---|---|
| author | Lu Wang Li Ding Gang Chen Zhou Xu Yanqing Zhang Bin Deng Xiya Wang Yemin Xu Mengyue Wu Yinhe Xia Zhennan Cao Ruilong Song |
| author_facet | Lu Wang Li Ding Gang Chen Zhou Xu Yanqing Zhang Bin Deng Xiya Wang Yemin Xu Mengyue Wu Yinhe Xia Zhennan Cao Ruilong Song |
| author_sort | Lu Wang |
| collection | DOAJ |
| description | Background Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.Methods In this study, liposomal arachidonyl trifluoromethyl ketone (ATK) was anchored onto the adoptive T cell surface via bioorthogonal reactions, aiming to specifically inhibit the group IVA cytosolic phospholipase A2α (cPLA2α), a key enzyme facilitating phospholipid metabolism and senescent state of T cells.Results The surface engineering exerted rare side effects on the activation and migration of T cells, but local and sustained extravasation of ATK downregulated cPLA2α expression, reprogrammed lipid metabolism, and inhibited lipid droplet accumulation. This endows T cells with delayed senescence and declined apoptosis to maintain their tumor-killing potency. Systemic administration of surface-engineered T cells resulted in superior infiltration in solid tumors and improved antitumor efficacy by enhancing the secretion of cytotoxic molecules, thereby prolonging the survival of mice bearing colorectal carcinoma and melanoma xenografts.Conclusions Lipid-metabolically remodeled T cells with delayed senescence increase efficacy in tumor microenvironment, highlighting a novel strategy for solid tumor immunotherapy. |
| format | Article |
| id | doaj-art-de00f826a00746f78292216def560f9d |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-de00f826a00746f78292216def560f9d2025-01-07T08:00:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010403Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumorsLu Wang0Li Ding1Gang Chen2Zhou Xu3Yanqing Zhang4Bin Deng5Xiya Wang6Yemin Xu7Mengyue Wu8Yinhe Xia9Zhennan Cao10Ruilong Song11Department of Gastroenterology, Northern Jiangsu People`s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaCollege of Bioscience and Biotechnology, Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaQingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong, People`s Republic of ChinaQingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong, People`s Republic of ChinaMedical College, Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaDepartment of Gastroenterology, Northern Jiangsu People`s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaDepartment of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaDepartment of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaDepartment of Anesthesiology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaQingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, Shandong, People`s Republic of ChinaDepartment of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaInstitute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People`s Republic of ChinaBackground Tumor cells can drive the senescence of effector T cells by unbalancing their lipid metabolism, thereby limiting adoptive T cell therapy and contributing to tumor immune evasion. Our objective is to provide a feasible strategy for enhancing T cell treatment efficacy against solid tumors.Methods In this study, liposomal arachidonyl trifluoromethyl ketone (ATK) was anchored onto the adoptive T cell surface via bioorthogonal reactions, aiming to specifically inhibit the group IVA cytosolic phospholipase A2α (cPLA2α), a key enzyme facilitating phospholipid metabolism and senescent state of T cells.Results The surface engineering exerted rare side effects on the activation and migration of T cells, but local and sustained extravasation of ATK downregulated cPLA2α expression, reprogrammed lipid metabolism, and inhibited lipid droplet accumulation. This endows T cells with delayed senescence and declined apoptosis to maintain their tumor-killing potency. Systemic administration of surface-engineered T cells resulted in superior infiltration in solid tumors and improved antitumor efficacy by enhancing the secretion of cytotoxic molecules, thereby prolonging the survival of mice bearing colorectal carcinoma and melanoma xenografts.Conclusions Lipid-metabolically remodeled T cells with delayed senescence increase efficacy in tumor microenvironment, highlighting a novel strategy for solid tumor immunotherapy.https://jitc.bmj.com/content/13/1/e010403.full |
| spellingShingle | Lu Wang Li Ding Gang Chen Zhou Xu Yanqing Zhang Bin Deng Xiya Wang Yemin Xu Mengyue Wu Yinhe Xia Zhennan Cao Ruilong Song Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors Journal for ImmunoTherapy of Cancer |
| title | Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors |
| title_full | Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors |
| title_fullStr | Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors |
| title_full_unstemmed | Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors |
| title_short | Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors |
| title_sort | lipid metabolic remodeling delays senescence of t cells to potentiate their immunity against solid tumors |
| url | https://jitc.bmj.com/content/13/1/e010403.full |
| work_keys_str_mv | AT luwang lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT liding lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT gangchen lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT zhouxu lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT yanqingzhang lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT bindeng lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT xiyawang lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT yeminxu lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT mengyuewu lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT yinhexia lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT zhennancao lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors AT ruilongsong lipidmetabolicremodelingdelayssenescenceoftcellstopotentiatetheirimmunityagainstsolidtumors |