Researchers tested new CAR designs in NK-92 cells and found the modified cells killed tumor cells more effectively, showing stronger anti-cancer activity.
Researchers at the Ribeirão Preto Blood Center and the Center for Cell-Based Therapy (CTC) are exploring a key question in cancer immunotherapy: how to “wire” engineered natural killer (NK) cells so they respond faster and hit harder when they encounter a tumor.
Using the NK-92 cell line, the team tested new chimeric antigen receptor (CAR) designs that include specific costimulatory domains, such as 2B4 and DAP12. These domains act like internal activation circuits, shaping how strongly an NK cell ramps up its attack once the CAR recognizes a target.
In the experiments, adding 2B4 and DAP12 helped put the cells in a more aggressive state, making them “ready to attack” and improving their ability to destroy tumors. The results were published in Frontiers in Immunology.
The CTC is one of the Research, Innovation, and Dissemination Centers (RIDCs) funded by FAPESP. It operates within the Ribeirão Preto Blood Center and is affiliated with the general and teaching hospital (“Hospital das Clínicas”) of the Ribeirão Preto Medical School at the University of São Paulo (FMRP-USP).
Advancing CAR-NK Cell Design
CAR-based therapies have already changed outcomes for some cancers, especially hematological tumors, but most of what scientists know about the best internal signaling components comes from CAR-T cells. NK cells work differently, relying on a separate set of activation pathways, so translating CAR-T “recipes” to CAR-NK cells is not straightforward.
This study highlights how fine-tuning the costimulatory signals inside CAR-NK cells could make these therapies more potent and more consistent.
The researchers also explored a practical way to manage that power: temporary pharmacological control using dasatinib. Rather than permanently altering the cells, dasatinib was used as a short-term tool to modulate activation.
According to the Ribeirão Preto Blood Center Press Office, animal models showed that CAR-NK cells built with 2B4-DAP12 and pretreated with dasatinib achieved better tumor control than traditional versions. Together, the findings point toward CAR-NK treatments that are not only stronger, but also more controllable, which is a major goal for next-generation cell therapies.
DOI: 10.3389/fimmu.2025.1675877
Funding: São Paulo Research Foundation
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