CELL INTELLIGENCE · 肿瘤细胞治疗研究

T-cell based immunotherapies such as chimeric antigen receptor T (CAR-T) cell therapy face substantial hurdles when confronting solid tumors such as ovarian cancer, where metabolic constraints in the tumor microenvironment limit T cell infiltration and function. In particular, T cells exposed to nutrient deprivation and hypoxia upregulate autophagy, a lysosomal degradation pathway that negatively regulates effector responses.

Here, we used CRISPR-Cas9 to target a folate receptor alpha ( FR) CAR expression cassette into the locus of the essential autophagy gene ATG5 , thereby generating autophagy-deficient CAR-T cells in a single editing step. Targeted metabolite profiling revealed that deletion of ATG5 induced widespread metabolic reprogramming characterized by increased glucose and amino acid uptake.

Functionally, ATG5 -knockout CAR-T cells maintained high cytolytic activity when assayed in patient-derived ascites in vitro , and exhibited superior and long-lasting tumor control against ovarian tumors in vivo . Taken together, our results suggest that deletion of ATG5 metabolically primes CAR-T cells for enhanced cytotoxicity in immune-suppressive conditions, thereby improving the therapeutic potential of FR CAR-T cells for ovarian cancer immunotherapy.