Platycodin D reduces PD‐L1 levels by inhibiting LXR‐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.