ArticleFrontiers in immunology2026
Tunable CAR-NK-92 activity in the tumor microenvironment via a dual ATF4-responsive circuit.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Chimeric antigen receptor-engineered NK-92 (CAR-NK-92) cells emulate activated natural killer cells, combining potent innate cytotoxicity with CAR-driven antigen specificity. Their scalability and FDA approval make them attractive for universal use. However, their application in solid tumors remains limited by the immunosuppressive tumor microenvironment (TME), which is often characterized by hypoxia and nutrient deprivation. We recently demonstrated that an ATF4-inducible promoter, 2xAARE-YB, enables spatial and temporal control of CAR expression in T cells, enhancing safety by restricting expression to amino acid-deprived TME while reducing exhaustion to improve persistence. In this study, we adapted the 2xAARE-YB system for CAR-NK-92 cells. Under glucose-limited conditions, a hallmark of the TME, the system effectively regulated CAR expression, enabling potent antigen-specific cytotoxicity. In xenograft models, the nutrient-responsive 2xAARE-YB system achieved regulated intratumoral CAR expression
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