Oncology · 2 h ago
BAZ2A-driven palmitate accumulation linked to CAR-T dysfunction in renal cancer model
A preclinical study used an in vivo CRISPR screen in a mouse renal cell carcinoma model to identify BAZ2A as a mediator of resistance to CD70-targeted CAR-T therapy. The researchers report that tumor-derived palmitic acid impairs CAR-T-cell mitochondrial function, while pharmacologic BAZ2A inhibition reduced lipid accumulation and restored CAR-T activity in vivo.
- BAZ2A was identified in an in vivo CRISPR screen.
- Tumor palmitate impaired CAR-T-cell mitochondrial fitness.
- BAZ2A inhibition restored CAR-T activity in mice.
- Findings are preclinical; clinical benefit is unestablished.
CAR-T therapy has shown limited efficacy in solid tumors, but tumor-intrinsic mechanisms of resistance remain incompletely defined. In a mouse renal cell carcinoma model, researchers conducted an in vivo CRISPR screen and identified the epigenetic regulator BAZ2A as a contributor to resistance to CD70-targeted CAR-T cells. The abstract does not report the number of animals or provide quantitative effect sizes.
The authors report that BAZ2A reprograms tumor lipid metabolism, promoting production and accumulation of palmitic acid in the tumor microenvironment. CAR-T cells take up the excess palmitate, which inhibits PGC-1α activity and impairs mitochondrial fitness, contributing to a dysfunctional state. Pharmacologic inhibition of BAZ2A reduced lipid accumulation and restored CAR-T-cell activity in vivo.
These findings identify a potential epigenetic–metabolic mechanism of immune resistance and a possible therapeutic target. The evidence described is preclinical and comes from a mouse renal cancer model; it does not establish efficacy or safety in people, or show that BAZ2A inhibition improves outcomes in patients receiving CAR-T therapy.
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Nature Cancer: BAZ2A-induced epigenetic states in cancer cells fuel palmitate accumulation in the tumor microenvironment driving CAR-T cell exhaustion ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.