Study Background and Disease Burden
Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide. Approximately 20%-30% of NSCLC patients harbor mutations in the tumor suppressor gene LKB1 (also known as STK11). LKB1-mutant NSCLC is characterized as an immunologically “cold” tumor with poor infiltration of cytotoxic T lymphocytes and resistance to immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies. This resistance leads to limited therapeutic options and poorer clinical outcomes for this patient subset. Therefore, novel strategies to overcome primary immunotherapy resistance in LKB1-mutant NSCLC are urgently needed.
Study Design
Led by Bai Xue, Wu Dehua, Dong Zhongyi, and Guo Xuejun at Southern Medical University Nanfang Hospital, the team conducted a series of preclinical investigations published in Cell Reports Medicine (August 2025). Using genetically engineered LKB1-deficient NSCLC cell lines and murine tumor models, they assessed the effects of high-dose ascorbic acid (vitamin C) on tumor cell viability, oxidative stress, and response to PD-1 checkpoint blockade. Key endpoints included measurement of reactive oxygen species (ROS), cell death phenotypes, immune cell infiltration in tumor tissues, and combinational therapy efficacy.
Key Findings
1. LKB1 Mutation Increases ROS Vulnerability and GLUT1 Expression
LKB1-deficient lung cancer cells show significantly elevated endogenous ROS levels compared to wild-type counterparts. The study identified that LKB1 mutation upregulates the glucose transporter GLUT1, facilitating increased uptake of oxidized vitamin C (dehydroascorbic acid) into tumor cells.
2. High-Dose Vitamin C Selectively Induces Pyroptosis in LKB1-Deficient Cells
Treatment with high-dose ascorbic acid (10 mM) further amplifies intracellular ROS and hydrogen peroxide levels in LKB1-mutant cells, activating caspase-3 and cleaving gasdermin E (GSDME), thereby triggering pyroptosis—a form of inflammatory programmed cell death characterized by membrane pore formation and cell lysis. Importantly, high-dose vitamin C does not induce pyroptosis in LKB1 wild-type NSCLC cells.
3. Vitamin C Enhances Immunotherapy Sensitivity Through Immune Microenvironment Modulation
In murine lung cancer models, high-dose vitamin C alone suppresses tumor growth modestly but significantly sensitizes LKB1-mutant tumors to PD-1 blockade. Analysis of tumor draining lymph nodes showed increased mature dendritic cells, while tumor tissues exhibited enhanced T cell infiltration and proliferation. These changes reflect improved antigen presentation and a more immunogenic tumor microenvironment facilitated by pyroptotic cell death.
4. GSDME-Mediated Pyroptosis Is Essential for Synergistic Therapy
Pharmacological inhibition of GSDME abrogates the synergistic antitumor effect of combined high-dose vitamin C and PD-1 inhibition, confirming the centrality of pyroptosis in mediating the enhanced immune response.
Expert Commentary
The study pioneeringly links oxidative stress augmentation via vitamin C and the induction of pyroptosis to overcome immune evasion in a notoriously resistant NSCLC subtype. The mechanism aligns with the understanding of LKB1’s crucial role in redox homeostasis and highlights how metabolic vulnerabilities can be therapeutically exploited. While clinical translation warrants cautious dose optimization and safety evaluation, this strategy offers a promising adjunct to current immunotherapeutic regimens for LKB1-mutant NSCLC.
Conclusion
This research reveals that high-dose ascorbic acid selectively induces pyroptosis in LKB1-mutant NSCLC by leveraging GLUT1-mediated vitamin C uptake and ROS-dependent caspase-3/GSDME activation. The resulting immunogenic cell death remodels the tumor microenvironment, enhancing dendritic cell activation and T cell-mediated immune responses, and overcoming primary resistance to PD-1 blockade. Ongoing phase II trials at Southern Medical University are evaluating the safety and efficacy of combining vitamin C, immunotherapy, and chemotherapy in this patient population. These findings have potentially significant clinical implications, offering a novel therapeutic avenue for improving outcomes in LKB1-mutant NSCLC patients.
References
Sun X, Cai X, Li S, et al. High-dose ascorbic acid selectively induces pyroptosis in LKB1-deficient lung cancer and sensitizes immunotherapy. Cell Rep Med. 2025;6(8):102291. doi:10.1016/j.xcrm.2025.102291
