APG-115 Induces SLC7A11-Mediated Ferroptosis and Upregulates PD-L1 Expression in Thyroid Cancer.

The murine double minute 2 (MDM2)-p53 interaction inhibitor APG-115 demonstrates therapeutic potential in advanced malignancies. However, its molecular mechanism, especially for programmed death ligand 1 (PD-L1) immunotherapy modulation, remains poorly understood in thyroid cancer (TC). Herein, we conducted a series of in vitro and in vivo studies to investigate the therapeutic effect of APG-115 and the underlying molecular mechanisms in TC. We performed Cell Counting Kit (CCK-8) and cell scratch assay to assess the effect of APG-115 on the biological behavior of TC cells. Meanwhile, we performed animal experiments to investigate the therapeutic effect of APG-115 on TC in vivo. TC patient-derived organoids were further used to evaluate the potential value for clinical application of APG-115. Our results showed that APG-115 exhibited beneficial therapeutic effects in TC both in vitro and in vivo. Mechanistically, APG-115 restored the p53 antitumor effects by blocking MDM2-p53 binding and upregulating the PD-L1 expression. APG-115 downregulated Solute Carrier Family 7 Member 11 (SLC7A11) expression, contributing to lipid peroxidation and affecting PD-L1 expression in TC. Our study expands the clinical application value of APG-115 in cancer treatment, especially by further exploring the complex interplay between APG-115, PD-L1 immunotherapy, and ferroptosis.