Michelolide Enhances the Anticancer Efficacy of Radiation by Downregulating PD-L1 Protein Levels in Tumor Cells

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Breast cancer exhibits high incidence and mortality rates in women.
• Programmed death-ligand 1 (PD-L1) facilitates tumor immune evasion by suppressing T cell activity.
• Micheliolide (MCL) is a sesquiterpene lactone with diverse biological activities.

Purpose of the Study:

• To investigate the effect of MCL on PD-L1 expression in breast cancer.
• To elucidate the molecular mechanisms underlying MCL's action on PD-L1.
• To evaluate MCL's potential in combination with radiotherapy for breast cancer treatment.

Main Methods:

• In vitro studies on breast cancer cells assessing PD-L1 expression.
• Bioinformatics analysis and shRNA interference to identify signaling pathways.
• In vivo experiments using syngeneic tumor models in mice.

Main Results:

• Radiation was found to upregulate PD-L1 expression in breast cancer cells.
• MCL pretreatment inhibited radiation-induced PD-L1 upregulation.
• MCL suppressed the IRF1-STAT1 signaling pathway, reducing PD-L1 transcription and accelerating its proteasomal degradation.
• Combined MCL and radiotherapy significantly inhibited tumor growth and increased intratumoral CD8+ T cell infiltration.

Conclusions:

• MCL acts as an immunomodulator and radiosensitizer in breast cancer.
• MCL enhances T-cell-mediated antitumor immunity by modulating PD-L1 expression.
• MCL improves radiotherapy efficacy through inhibition of the IRF1-STAT1 pathway and promotion of PD-L1 degradation.