Platycodin D reduces <scp>PD</scp> ‐ <scp>L1</scp> levels by inhibiting <scp>LXR</scp> ‐β activity and combines with nintedanib to enhance the tumor‐killing effect of T cells

Most tumors are resistant to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors, which may be due to impaired antigen presentation resulting from the downregulation of major histocompatibility complex class I (MHC-I) expression on tumor cells. We observed that platycodin D (PD), polygalacin D, and platycodin D2, which are plant-derived triterpenoid saponins, significantly reduced PD-L1 levels. RNA sequencing and the PharmMapper database analysis identified liver X receptor β (LXR-β) as a potential PD target. Further studies showed that PD reduces PD-L1 levels by binding to LXR-β and inhibiting LXR-β activity. Coadministration of PD and nintedanib, known to upregulate MHC-I expression, enhanced tumor recognition and killing by T cells. This study provides new insights into PD applications and mechanisms.