The Phospholipid Bis(monoacylglycero)Phosphate Confers Antitumour Immunogenicity to Exosomes Secreted by Dendrogenin A, Which Activates Its Biosynthesis in Tumour Cells

Dendrogenin A (DDA) is a cholesterol-derived antitumour metabolite that promotes the secretion of immunogenic antitumour exosomes (DDA-sEV) enriched in bis(monoacylglycero)phosphate (BMP). BMP is a phospholipid specific to late endosomes and lysosomes, where it plays a crucial role in lipid degradation, regulates the fate of endosomal cholesterol, and contributes to intraluminal vesicle formation. Dysregulation of BMP biosynthesis is associated with multiple diseases. Here, we show that the DDA/LXRβ complex activates the transcription and activity of phospholipase D (PLD) and CLN5, two enzymes involved in BMP biosynthesis. Inhibition of PLD in DDA-treated tumour cells reduces BMP levels in DDA-sEV, impairs their release, and their antitumour immune activity. Blocking BMP on DDA-sEV with a specific antibody abolishes their antitumour reponse, prevents the recruitment of activated dendritic cells (DC) and T cells into tumours, and decreases mouse survival. This blockade also impairs DDA-sEV uptake by immature DC (iDC) and hinders DC maturation and Th1 T cell activation. Notably, neutralising the BMP-presenting receptor on iDC inhibits DDA-sEV uptake and DC maturation. Treatment of iDC with free BMP induces their functional maturation, confirming BMP as a key immune activator. Furthermore, BMP-containing DDA-sEV enhance the efficacy of anti-PD-1 therapy in melanoma. Targeting LXRβ with DDA represents an innovative strategy to stimulate anticancer immunity by increasing BMP levels in tumours and sEV.