Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells
Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cance...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000684 |
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| author | Zhiwei Yuan Taiyan Yu Xu Wang Kelin Meng Tianlai Wang Boyu Wang Yu Xi Congjian Wang Chenxi Zeng Shaojie Hu Yitao Tian Hui Xiong Qi Wang Wenbin Zou Xue Wang Yi Gao Xiangning Fu Lequn Li |
| author_facet | Zhiwei Yuan Taiyan Yu Xu Wang Kelin Meng Tianlai Wang Boyu Wang Yu Xi Congjian Wang Chenxi Zeng Shaojie Hu Yitao Tian Hui Xiong Qi Wang Wenbin Zou Xue Wang Yi Gao Xiangning Fu Lequn Li |
| author_sort | Zhiwei Yuan |
| collection | DOAJ |
| description | Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation. |
| format | Article |
| id | doaj-art-9c8c5bfe9ea6473d8a025aaa9c00ae1e |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-9c8c5bfe9ea6473d8a025aaa9c00ae1e2025-02-08T04:59:56ZengElsevierPharmacological Research1096-11862025-03-01213107643Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cellsZhiwei Yuan0Taiyan Yu1Xu Wang2Kelin Meng3Tianlai Wang4Boyu Wang5Yu Xi6Congjian Wang7Chenxi Zeng8Shaojie Hu9Yitao Tian10Hui Xiong11Qi Wang12Wenbin Zou13Xue Wang14Yi Gao15Xiangning Fu16Lequn Li17Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaThoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCorrespondence to: Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Department of Thoracic Surgery, 1095 Jie Fang Avenue, Wuhan, Hubei 430030, China.; Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCorrespondence to: Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Department of Thoracic Surgery, 1095 Jie Fang Avenue, Wuhan, Hubei 430030, China.; Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaGlutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.http://www.sciencedirect.com/science/article/pii/S1043661825000684Glutamine metabolismIFN-γ signalingNon-small cell lung cancerAutophagyImmunotherapyV9302 |
| spellingShingle | Zhiwei Yuan Taiyan Yu Xu Wang Kelin Meng Tianlai Wang Boyu Wang Yu Xi Congjian Wang Chenxi Zeng Shaojie Hu Yitao Tian Hui Xiong Qi Wang Wenbin Zou Xue Wang Yi Gao Xiangning Fu Lequn Li Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells Pharmacological Research Glutamine metabolism IFN-γ signaling Non-small cell lung cancer Autophagy Immunotherapy V9302 |
| title | Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells |
| title_full | Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells |
| title_fullStr | Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells |
| title_full_unstemmed | Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells |
| title_short | Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells |
| title_sort | glutamine deprivation confers immunotherapy resistance by inhibiting ifn γ signaling in cancer cells |
| topic | Glutamine metabolism IFN-γ signaling Non-small cell lung cancer Autophagy Immunotherapy V9302 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000684 |
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