TY - JOUR
T1 - Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in non-small cell lung cancer
AU - Wang, Peng
AU - Zhang, Shengdan
AU - Chen, Xin
AU - Yang, Xu-Dong
AU - Huang, Shi
AU - Yin, Huiyong
AU - Duan, Hao-Yu
AU - Zhou, Fuling
AU - Yu, Jia
AU - Zhong, Bo
AU - Lin, Dandan
N1 - © The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.
PY - 2026/5
Y1 - 2026/5
N2 - Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here, we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.
© The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.
AB - Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here, we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.
© The Author(s) 2025. Published by Oxford University Press on behalf of Higher Education Press.
KW - Ferroptosis/immunology
KW - Animals
KW - Carcinoma, Non-Small-Cell Lung/immunology
KW - Lung Neoplasms/immunology
KW - Phospholipid Hydroperoxide Glutathione Peroxidase/genetics
KW - Mice
KW - Triglycerides/metabolism
KW - Humans
KW - Diacylglycerol O-Acyltransferase/genetics
KW - Cell Line, Tumor
KW - Tumor Microenvironment
KW - Mice, Knockout
UR - http://www.scopus.com/inward/record.url?scp=105038540245&partnerID=8YFLogxK
UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105038540245&origin=recordpage
U2 - 10.1093/procel/pwaf101
DO - 10.1093/procel/pwaf101
M3 - RGC 21 - Publication in refereed journal
C2 - 41259048
SN - 1674-800X
VL - 17
SP - 421
EP - 437
JO - Protein and Cell
JF - Protein and Cell
IS - 5
ER -
SDG 3 Good Health and Well-being