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A marine-derived small molecule induces immunogenic cell death against triple-negative breast cancer through ER
Haiyan Wen1, Yinxian Zhong1, Yuping Yin1
1Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, PR China.
Abstract:
Although triple-negative breast cancer (TNBC) is the most refractory subtype among all breast cancers, it has been shown to have higher immune infiltration than other subtypes. We identified the marine-derived small molecule MHO7, which acts as a potent immunogenic cell death (ICD) inducer through the endoplasmic reticulum (ER) stress-C/EBP-homologous protein (CHOP) pathway, to treat TNBC. MHO7 exerted cytostatic and cytotoxic effects on TNBC cells at an IC50 of 0.96-1.75 µM and suppressed tumor growth with an approximately 80% inhibition rate at a dose of 60 mg/kg. In 4T1 cell tumor-bearing mice, 30 mg/kg MHO7 inhibited pulmonary metastasis with an efficacy of 70.26%. Transcriptome analyses revealed that MHO7 changed the transcription of genes related to ribosome and protein processes in the ER. MHO7 also triggered reactive oxygen species (ROS) generation and attenuated glutathione (GSH) levels, which caused excessive oxidative stress and ER stress via the PERK/eIF2α/AFT4/CHOP pathway and led to cell apoptosis. ER stress and ROS production facilitated the release of ICD-related danger-associated molecular patterns (DAMPs) from TNBC cells, which activated the immune response in vivo, as indicated by the release of antitumor cytokines such as IL-6, IL-1β, IFN-γ, and TNF-α, increases in CD86+ and MHC-II dendritic cells and CD4+ and CD8+ T cells and a decrease in regulatory T cells (Tregs). These results reveal that MHO7 triggers an aggressive stress response to amplify tumor immunogenicity and induce a robust immune response. This synergistic effect inhibits primary breast cancer growth and spontaneous metastasis in TNBC, providing a new strategy for TNBC treatment.
Insights
Marine-derived MHO7 induces immunogenic cell death in triple-negative breast cancer (TNBC) by triggering endoplasmic reticulum (ER) stress. This novel approach enhances anti-tumor immunity, inhibiting TNBC growth and metastasis.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
- TNBC exhibits higher immune infiltration, suggesting potential for immunotherapy.
- Targeting immunogenic cell death (ICD) can enhance anti-tumor immune responses.
Purpose of the Study:
- To investigate the therapeutic potential of marine-derived MHO7 in TNBC.
- To elucidate the mechanism of MHO7-induced cell death and immune activation.
Main Methods:
- In vitro studies on TNBC cell lines to determine IC50 values and assess cytostatic/cytotoxic effects.
- In vivo studies using 4T1 tumor-bearing mice to evaluate tumor growth inhibition and metastasis suppression.
- Transcriptome analysis to identify molecular pathways affected by MHO7.
- Measurement of reactive oxygen species (ROS), glutathione (GSH) levels, and endoplasmic reticulum (ER) stress markers.
- Analysis of immune cell populations and cytokine release in response to MHO7 treatment.
Main Results:
- MHO7 demonstrated potent cytostatic and cytotoxic effects on TNBC cells (IC50: 0.96-1.75 µM).
- MHO7 significantly suppressed primary tumor growth (~80% inhibition) and pulmonary metastasis (~70% efficacy) in vivo.
- MHO7 induced ER stress via the PERK/eIF2α/AFT4/CHOP pathway, leading to apoptosis.
- MHO7 triggered ROS generation, attenuated GSH levels, and promoted ICD by releasing danger-associated molecular patterns (DAMPs).
- MHO7 treatment enhanced anti-tumor immunity, characterized by increased pro-inflammatory cytokines (IL-6, IL-1β, IFN-γ, TNF-α) and activated immune cells (dendritic cells, CD4+, CD8+ T cells), while decreasing regulatory T cells (Tregs).
Conclusions:
- MHO7 acts as a potent inducer of ICD in TNBC through ER stress and oxidative stress.
- MHO7 amplifies tumor immunogenicity, leading to a robust immune response against primary tumors and metastasis.
- MHO7 represents a promising novel therapeutic strategy for TNBC treatment.
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