BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion
Menée à l'aide d'un modèle murin de carcinome à cellules rénales, cette étude met en évidence un mécanisme par lequel le régulateur épigénétique BAZ2A favorise l'épuisement des lymphocytes CAR-T ciblant CD70 via la production et l'accumulation d'acide palmitique dans le microenvironnement tumoral, la captation de l'excès d'acide palmitique par les lymphocytes CAR-T, l'inhibition du coactivateur transcriptionnel PGC-1 alpha puis l'altération fonctionnelle des mitochondries
Chimeric antigen receptor T (CAR-T) cell therapy shows limited efficacy in solid tumors, partly owing to poorly defined tumor-intrinsic resistance mechanisms. Here we show that the epigenetic regulator BAZ2A drives resistance to CD70-targeted CAR-T therapy by reprogramming tumor lipid metabolism. Using an in vivo CRISPR screen in a mouse renal cell carcinoma model, we identify BAZ2A as a key mediator that promotes the production and accumulation of palmitic acid, a saturated fatty acid in the tumor microenvironment. Excess palmitic acid is taken up by CAR-T cells and impairs mitochondrial fitness by inhibiting PGC-1α activity, thereby enforcing a dysfunctional state. Pharmacologic inhibition of BAZ2A reduces lipid accumulation and restores CAR-T cell activity in vivo. These findings reveal an epigenetic–metabolic mechanism of immune resistance and suggest that targeting tumor lipid remodeling represents a therapeutic strategy to overcome CAR-T resistance in solid tumors.
Nature Cancer , résumé, 2026