GPX4 Defines an Immune-Cold Phenotype and Poor Prognosis in Resected Lung AdenocarcinomaOA
Objectives:Ferroptosis resistance may contribute to tumor progression and immune escape.This study evaluated the prognostic and immunological significance of glutathione peroxidase 4(GPX4),a core ferroptosissuppressive enzyme,in surgically resected lung adenocarcinoma.Methods:We retrospectively analyzed 104 patients with primary lung adenocarcinoma who underwent curative resection.GPX4 protein expression was assessed by immunohistochemistry(IHC)using the histological score(H-score),and patients were classified as GPX4-low(n=54)or GPX4-high(n=50).Intratumoral immune contexture was quantified using CD3,CD4,CD8,CD68,programmed cell death protein 1(PD-1),and programmed death-ligand 1(PD-L1)staining.Disease-free survival(DFS)and overall survival(OS)were analyzed using Cox regression.Cutoff sensitivity analyses,category consolidation,ridge-penalized Cox regression,events-per-variable assessment,bootstrap internal validation,and interobserver reproducibility testing were performed to strengthen statistical robustness.Results:GPX4-high tumors were associated with systemic inflammatory and immune-related features,including elevated fibrinogen(p=0.015),lower lymphocyte-to-monocyte ratio(p=0.003),and altered aspartate aminotransferase-to-alanine aminotransferase ratio(p=0.028).GPX4-high tumors showed reduced intratumoral CD3^(+),CD4^(+),CD8^(+),and CD68^(+)immune-cell infiltration,together with increased PD-1 and PD-L1 expression,indicating an immune-cold yet checkpoint-enriched phenotype.After category consolidation and ridge-penalized multivariable adjustment,high GPX4 expression remained independently associated with worse DFS(HR,8.63;95%CI,2.99-24.91;p<0.001)and OS(HR,6.94;95%CI,2.44-19.74;p<0.001).GPX4-based prognostic models showed bias-corrected C-index values of 0.782 for DFS and 0.826 for OS,with calibration slopes of 0.964 and 0.937,respectively.Conclusions:High GPX4 expression identifies a clinically adverse,ferroptosis-resistant,immune-remodeled phenotype in resected lung adenocarcinoma.Integrating GPX4 with clinicopathological and inflammatory variables may improve postoperative risk stratification.
Ganxin Wang;Zhongan Liu;Tian Zhou;Boting Yang;Jiaqin Chen;Jing Chen;Kai Huang;Yunqing Xu;Quan Tang;Xiangqian Yin;Guangqin Xiao;Sijia Zhang
Cancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,ChinaCancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,ChinaDepartment of Infectious Diseases,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,ChinaCancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China Department of Biophysics,Center for Integrative Physiology and Molecular Medicine(CIPMM),School of Medicine,Saarland University,Homburg,Germany Department of Biomedical Sciences,Institute for Health Research and Education,Osnabrück University,Osnabrück,GermanyCancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China Department of Biophysics,Center for Integrative Physiology and Molecular Medicine(CIPMM),School of Medicine,Saarland University,Homburg,Germany Department of Biomedical Sciences,Institute for Health Research and Education,Osnabrück University,Osnabrück,GermanyDepartment of Infectious Diseases,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,ChinaDepartment of Oncology,People’s Hospital of Huangpi District,Jianghan University,Wuhan,ChinaDepartment of Oncology,People’s Hospital of Huangpi District,Jianghan University,Wuhan,ChinaDepartment of Oncology,Hubei Aerospace Hospital,Xiaogan,ChinaDepartment of Oncology,People’s Hospital of Huangpi District,Jianghan University,Wuhan,ChinaCancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,ChinaCancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China Department of Biophysics,Center for Integrative Physiology and Molecular Medicine(CIPMM),School of Medicine,Saarland University,Homburg,Germany Department of Biomedical Sciences,Institute for Health Research and Education,Osnabrück University,Osnabrück,Germany
医药卫生
Lung adenocarcinomaGPX4tumor immune microenvironmentPD-L1nomogram
《Oncology Research》 2026 (8)
P.566-589,24
supported by grants from the National Natural Science Foundation of China(Nos.81402197,81600482,and 82570789)the Natural Science Foundation of Hubei Province(Nos.2019CFB501,2020CFB600,and 2024 AFB663)the China Postdoctoral Science Foundation(Nos.2018M632875 and 2019T120671)the China Scholarship Council(CSC)(No.202306160006).
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