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Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer
Lisha Wu1, Shoumin Bai1,2, Jing Huang3
1Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Abstract:
Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.
Insights
Nigericin induces cell death in triple-negative breast cancer (TNBC) by triggering pyroptosis and apoptosis. This antibiotic enhances anti-tumor immunity and shows promise when combined with immune checkpoint inhibitors for TNBC treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Advanced triple-negative breast cancer (TNBC) has limited treatment options.
- Immune checkpoint inhibitors (ICIs) show efficacy but have low response rates in TNBC.
- Novel therapeutic strategies are needed to improve outcomes for TNBC patients.
Purpose of the Study:
- To investigate the anti-cancer effects of nigericin in TNBC.
- To elucidate the mechanisms underlying nigericin-induced cell death.
- To evaluate the potential of nigericin in combination with ICIs for TNBC treatment.
Main Methods:
- Treatment of TNBC cell lines (MDA-MB-231, 4T1) with nigericin.
- Analysis of cell death pathways (pyroptosis, apoptosis) and mitochondrial function.
- Assessment of immune cell infiltration and anti-tumor activity in vivo.
- Combination therapy studies with anti-PD-1 antibody.
Main Results:
- Nigericin induced concurrent pyroptosis and apoptosis in TNBC cells.
- Nigericin caused potassium efflux, mitochondrial dysfunction, and ROS production.
- Nigericin enhanced CD4+ and CD8+ T cell infiltration and anti-tumor effects.
- Nigericin demonstrated synergistic effects with anti-PD-1 antibody in TNBC treatment.
Conclusions:
- Nigericin is a potent inducer of pyroptosis and apoptosis in TNBC cells.
- Nigericin enhances anti-tumor immunity, suggesting a role in immunotherapy.
- Nigericin represents a promising therapeutic agent, particularly in combination with ICIs for advanced TNBC.
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