Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

作者：Feng Liu, Qian Zhou, Haifeng Jiang, Tingting Zhang, Cheng Miao, Xiaohong Xu, Jiaxing Wu, Song-lin Yin, Xu Shijie, Jingyi Peng, Panpan Gao, Xuan Cao, Feng Pan, Ximiao He, Xiaoqian Chen · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02686-1 · 被引用次数：29 · 研究领域：Glioma Diagnosis and Treatment、Brain Metastases and Treatment、Piperaceae Chemical and Biological Studies

Abstract Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422 TN -GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422 TN -GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422 TN ) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422 TN -tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422 TN -mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-P...