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

Xiangyu Sun1, Xiaoting Cai1, Shangbiao Li2

  • 1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Cell Reports. Medicine
|August 16, 2025
PubMed

Insights

High-dose ascorbic acid (AA) can overcome immune checkpoint inhibitor (ICI) resistance in LKB1-deficient non-small cell lung cancers (NSCLCs). This occurs by inducing pyroptosis and enhancing anti-tumor immunity via dendritic cell maturation.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Metabolism

Background:

  • Liver kinase B1 (LKB1) deficiency in non-small cell lung cancers (NSCLCs) confers primary resistance to immune checkpoint inhibitors (ICIs).
  • Tumor redox imbalance presents a potential therapeutic vulnerability in these resistant NSCLCs.

Purpose of the Study:

  • To investigate the therapeutic potential of high-dose ascorbic acid (AA) in LKB1-deficient NSCLCs.
  • To elucidate the mechanisms by which AA affects redox balance, cell death, and immune responses in NSCLC.

Main Methods:

  • Utilized pre-clinical NSCLC models with LKB1 deficiency.
  • Administered high-dose ascorbic acid (AA) and immune checkpoint inhibitors (ICIs).
  • Analyzed tumor redox status, pyroptosis markers (caspase-3, gasdermin-E), immune cell infiltration (TCF1+CD8+ T cells), and dendritic cell (DC) function.

Main Results:

  • LKB1 deficiency upregulates GLUT1, increasing AA accumulation and exacerbating redox imbalance in NSCLC cells.
  • High-dose AA triggers pyroptosis via the H2O2/ROS-caspase-3-GSDME axis in LKB1-deficient NSCLCs.
  • AA treatment reverses ICI resistance, promoting TCF1+CD8+ T cell (Tpex) infiltration and DC maturation, which is dependent on CD103+ DCs.

Conclusions:

  • High-dose AA can overcome ICI resistance in LKB1-deficient NSCLCs by inducing pyroptosis and immunogenic cell death.
  • AA-induced pyroptosis drives Tpex cell expansion and anti-tumor immunity through DC maturation.
  • Gasdermin-E (GSDME) is critical for pyroptosis-driven anti-tumor immunity, supporting clinical trials combining ICIs with high-dose AA.
Keywords:
GSDMELKB1-deficient lung cancerTpexcaspase-3dendritic cellshigh-dose ascorbic acidimmunotherapy resistancepyroptosisreactive oxygen species

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