BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion.

BAZ2A reprograms lipid metabolism in a mouse renal cell carcinoma model, promoting palmitic acid accumulation in the tumor microenvironment that impairs CAR-T function.

• Why it matters: Solid tumors limit CAR-T efficacy, and tumor-intrinsic resistance mechanisms are not well defined, especially those linking epigenetic control to immune failure.
• What they did: An in vivo CRISPR screen in a mouse renal cell carcinoma model identified BAZ2A as a mediator of palmitic acid production and accumulation; CAR-T uptake was linked to reduced mitochondrial fitness via PGC-1α activity.
• The result: Pharmacologic inhibition of BAZ2A reduced lipid accumulation and restored CAR-T activity in vivo, revealing an epigenetic-metabolic immune resistance mechanism and a potential targeting strategy.

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