High-dose ascorbic acid selectively induces pyroptosis in LKB1-deficient lung cancer and sensitizes immunotherapy
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 H<sub>2</sub>O<sub>2</sub>/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)<sup>+</sup>CD8<sup>+</sup> T cell (progenitor-exhausted CD8<sup>+</sup> T cell [Tpex]) infiltration. Pyroptosis-driven immunogenic cell death (ICD) promotes cross-presenting dendritic cell (DC) maturation, which drives Tpex proliferation. Crucially, in Batf3<sup>-/-</sup> mice lacking functional CD103<sup>+</sup> 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.
Authors
- Xue‐Jun Guo (ORCID: https://orcid.org/0000-0003-0409-9100)
- Shangbiao Li (ORCID: https://orcid.org/0000-0002-7536-5552)
- P. Wang (ORCID: https://orcid.org/0000-0001-9353-6952)
- Zi-Xuan Rong (ORCID: https://orcid.org/0000-0001-5686-0796)
- Jiayu Jiang (ORCID: https://orcid.org/0009-0002-7237-8523)
- Ruozheng Pi
- Jingrong Xiong
- Jia-Le Tan (ORCID: https://orcid.org/0000-0003-0484-5978)
- Duan-Duan Han (ORCID: https://orcid.org/0000-0001-8718-2174)
- Dehua Wu (ORCID: https://orcid.org/0000-0003-0560-0016)
- Hanxu Ai (ORCID: https://orcid.org/0009-0005-3764-2765)
- Zhong‐Yi Dong (ORCID: https://orcid.org/0000-0001-9967-0060)
- Jiaqi Chen (ORCID: https://orcid.org/0009-0005-3030-4253)
- Zhilin Zou (ORCID: https://orcid.org/0000-0002-4772-0027)
- Yan-Pei Zhang (ORCID: https://orcid.org/0000-0002-8025-5681)
- Xiao-Ting Cai (ORCID: https://orcid.org/0000-0001-9989-3571)
- Zhihong Liu (ORCID: https://orcid.org/0000-0001-6093-0726)
- Xiaonan Zhang (ORCID: https://orcid.org/0000-0003-0155-776X)
- Xiangyu Sun (ORCID: https://orcid.org/0009-0002-8750-0405)
- Yanping Lin (ORCID: https://orcid.org/0000-0001-6260-7666)
- Xue Bai (ORCID: https://orcid.org/0000-0001-5725-2442)
- Ze‐Qin Guo
- Zihang Yu (ORCID: https://orcid.org/0009-0005-7385-8336)
- Fangfang Kang
Institutions
- Nanfang Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102291
- Citations
- 6
- Primary Topic
- Vitamin C and Antioxidants Research
- Type
- article
- Field-Weighted Citation Impact
- 6.72
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Guangdong Province
- Guangzhou Science and Technology Program key projects
- Basic and Applied Basic Research Foundation of Guangdong Province