2. Academic Validation
  3. High-dose ascorbic acid selectively induces pyroptosis in LKB1-deficient lung cancer and sensitizes immunotherapy

High-dose ascorbic acid selectively induces pyroptosis in LKB1-deficient lung cancer and sensitizes immunotherapy

  • Cell Rep Med. 2025 Aug 12:102291. doi: 10.1016/j.xcrm.2025.102291.
Xiangyu Sun 1,  Xiaoting Cai 1,  Shangbiao Li 2,  Ruozheng Pi 1,  Zeqin Guo 1,  Jiayu Jiang 1,  Pinhao Wang 1,  Jingrong Xiong 1,  Zhuangzhuang Liu 1,  Zixuan Rong 1,  Zihang Yu 1,  Xiaonan Zhang 1,  Jiaqi Chen 1,  Duanduan Han 1,  Yanpei Zhang 1,  Jiale Tan 1,  Yan Lin 1,  Zhuocheng Zou 1,  Haochen Ai 1,  Fangfang Kang 1,  Xuejun Guo 3,  Zhongyi Dong 4,  Dehua Wu 5,  Xue Bai 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Cell Biology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
  • 3 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: 576718933@qq.com.
  • 4 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: dongzy1317@foxmail.com.
  • 5 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: 18602062748@163.com.
  • 6 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: baixue1990@i.smu.edu.cn.
PMID: 40818456 DOI: 10.1016/j.xcrm.2025.102291
Abstract

Liver kinase B1 (LKB1)-deficient non-small cell lung cancers (NSCLCs) exhibit primary resistance to immune checkpoint inhibitors (ICIs). The redox imbalance inherent in these tumors may represent a potential therapeutic vulnerability. High-dose ascorbic acid (AA) could induce cell redox imbalance. Here, we uncover that LKB1 deficiency upregulates the transporter GLUT1, which enables the accumulation of AA, thereby exacerbating redox imbalance in NSCLC cells. This triggers Pyroptosis in LKB1-deficient NSCLC cells via the H2O2/Reactive Oxygen Species (ROS)-caspase-3-gasdermin-E (GSDME) axis. In pre-clinical models, high-dose AA reverses ICI resistance and remodels the immune microenvironment, characterized by T cell factor 1 (TCF1)+CD8+ T cell (progenitor-exhausted CD8+ T cell [Tpex]) infiltration. Pyroptosis-driven immunogenic cell death (ICD) promotes cross-presenting dendritic cell (DC) maturation, which drives Tpex proliferation. Crucially, in Batf3-/- mice lacking functional CD103+ DC populations, both Tpex expansion and therapeutic benefits are abrogated, confirming DC dependence. In addition, GSDME is validated as a gatekeeper of pyroptosis-driven antitumor immunity. This work provides a rationale for clinical trials combining ICI with high-dose AA.

Keywords

GSDME; LKB1-deficient lung cancer; Tpex; caspase-3; dendritic cells; high-dose ascorbic acid; immunotherapy resistance; pyroptosis; reactive oxygen species.

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