Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance
(1) Lei G (2) Lu Z (3) Xu Z (4) Braun C (5) Huo D (6) Gao J (7) Tan L (8) Hong T (9) Wu S (10) Sun M (11) Zhao X (12) Li Q (13) Chen X (14) Yan Y (15) Lee H (16) Mao C (17) Zhuang L (18) Ku LT (19) Puebla N (20) Barsoumian H (21) Yao J (22) Hong L (23) Zhang J (24) Tran H (25) Lee JJ (26) Gibbons D (27) Vaporciyan A (28) Heymach J (29) Lin C (30) Gottlieb E (31) You MJ (32) Welsh JW (33) Lin SH (34) Zang X (35) Li Z (36) Gan B
Lei, Lu, and Xu et al. showed that cuproptosis induced immunogenic cell death, releasing DAMPs that drove DC maturation, DC-dependent cross-priming, and M1-like TAM and effector CD8+ T cell remodeling, with enhanced tumor suppression in immunocompetent hosts. CD8+ T cell-derived IFNγ activated STAT1–IRF1 signaling to upregulate mitochondrial FDX1 in tumor cells, increasing protein lipoylation and sensitization to cuproptosis. In breast, lung, and pancreatic tumor models, combining cuproptosis inducers with anti-PD-L1 amplified tumoral cuproptosis, increased intratumoral CD8+ T cell functions, and overcame intrinsic and acquired ICB resistance.
Contributed by Shishir Pant
(1) Lei G (2) Lu Z (3) Xu Z (4) Braun C (5) Huo D (6) Gao J (7) Tan L (8) Hong T (9) Wu S (10) Sun M (11) Zhao X (12) Li Q (13) Chen X (14) Yan Y (15) Lee H (16) Mao C (17) Zhuang L (18) Ku LT (19) Puebla N (20) Barsoumian H (21) Yao J (22) Hong L (23) Zhang J (24) Tran H (25) Lee JJ (26) Gibbons D (27) Vaporciyan A (28) Heymach J (29) Lin C (30) Gottlieb E (31) You MJ (32) Welsh JW (33) Lin SH (34) Zang X (35) Li Z (36) Gan B
Lei, Lu, and Xu et al. showed that cuproptosis induced immunogenic cell death, releasing DAMPs that drove DC maturation, DC-dependent cross-priming, and M1-like TAM and effector CD8+ T cell remodeling, with enhanced tumor suppression in immunocompetent hosts. CD8+ T cell-derived IFNγ activated STAT1–IRF1 signaling to upregulate mitochondrial FDX1 in tumor cells, increasing protein lipoylation and sensitization to cuproptosis. In breast, lung, and pancreatic tumor models, combining cuproptosis inducers with anti-PD-L1 amplified tumoral cuproptosis, increased intratumoral CD8+ T cell functions, and overcame intrinsic and acquired ICB resistance.
Contributed by Shishir Pant
ABSTRACT: Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8(+) T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8(+) T cell-derived interferon (IFN)-_ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.
Author Info:
(1) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: guanglei_csu@163.com. (2) Departme
nt of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7) Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (12) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (14) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (15) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (16) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (17) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (18) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (19) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (20) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (23) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (24) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (25) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (26) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (27) Department of Thoracic and Cardiovascular Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (28) Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (29) Department of Molecular and Cellular Oncology, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (30) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (31) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. (32) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (33) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (34) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (35) Department of Biostatistics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (36) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: bgan@mdanderson.org.
