2. Academic Validation
  3. Lidocaine Modulates Cytokine Production and Reprograms the Tumor Immune Microenvironment to Enhance Anti-Tumor Immune Responses in Gastric Cancer

Lidocaine Modulates Cytokine Production and Reprograms the Tumor Immune Microenvironment to Enhance Anti-Tumor Immune Responses in Gastric Cancer

  • Int J Mol Sci. 2025 Mar 31;26(7):3236. doi: 10.3390/ijms26073236.
Yi-Ying Wu 1 2,  Ming-Shan Chen 3,  I-Chun Chen 4 5 6,  Feng-Hsu Wu 7 8 9,  Tsai-Ling Liao 10,  Hsiao-Wei Wen 11,  Brent L Nielsen 12,  Hung-Jen Liu 1 2 13 14
Affiliations

Affiliations

  • 1 Institute of Molecular Biology, National Chung Hsing University, Taichung 402, Taiwan.
  • 2 The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
  • 3 Department of Anesthesiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 600, Taiwan.
  • 4 Department of Psychiatry, Taichung Veterans General Hospital, Taichung 407, Taiwan.
  • 5 Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 6 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan.
  • 7 Division of General Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan.
  • 8 Department of Critical Care, Taichung Veterans General Hospital, Taichung 407, Taiwan.
  • 9 Department of Nursing, Hung Kuang University, Taichung 433, Taiwan.
  • 10 Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
  • 11 Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan.
  • 12 Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA.
  • 13 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan.
  • 14 Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan.
PMID: 40244064 DOI: 10.3390/ijms26073236
Abstract

Lidocaine, a local anesthetic, has been shown to modulate immune responses. This study examines its effects on cytokine production in peripheral blood mononuclear cells (PBMCs) from healthy donors and tumor-infiltrating immune cells (TIICs) from gastric Cancer patients. PBMCs from healthy donors and TIICs from gastric Cancer patients were treated with lidocaine. Cytokine production was assessed using flow cytometry and cytokine assays, with a focus on IFN-γ, IL-12, IL-10, TGF-β, and IL-35 levels. Cytotoxicity against primary gastric Cancer cells (PGCCs) was also evaluated. Lidocaine inhibited IFN-γ production in CD8+ PBMCs and IL-12 in CD14+ PBMCs while increasing anti-inflammatory cytokines (IL-10, TGF-β, IL-35) in CD4+CD25+ and CD14+ cells. In TIICs, lidocaine enhanced IFN-γ and IL-12 production in CD8+ and CD14+ cells while reducing IL-10, TGF-β, and IL-35 levels, promoting an M1-like phenotype in macrophages. Mechanistically, lidocaine enhanced IFN-γ production in sorted CD8+ TIICs through G-protein-coupled receptor (GPCR) signaling and increased IL-12 production in sorted CD14+ TIICs via the Toll-like Receptor 4 (TLR4) signaling pathway. Lidocaine also increased IFN-γ production and cytotoxicity in CD8+ TIICs via NF-κB activation. Importantly, lidocaine did not affect the viability of PBMCs, TIICs, or PGCCs at concentrations up to 1.5 mM. Lidocaine reprogrammed the tumor immune microenvironment, enhancing anti-tumor immune responses, suggesting its potential to modulate immune functions in gastric Cancer.

Keywords

IFN-γ production; M1 macrophages; NF-κB activation; cytokine modulation; gastric cancer; gastrointestinal disease; immune response; inflammation; lidocaine; tumor-infiltrating immune cells.

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