Cancer immunotherapy has another tweak on the table, and this one starts by making killer cells hit harder after a brief pause.

Researchers in Brazil say they have found a way to make natural killer, or NK, cells more powerful and precise by changing how engineered receptors activate them. In a study published in Frontiers in Immunology, scientists at the Ribeirão Preto Blood Center and the Center for Cell-Based Therapy used the NK-92 cell line to test new versions of chimeric antigen receptors, known as CARs.

The engineered receptors included costimulatory components such as 2B4 and DAP12, which help activate the cells. The researchers found those additions made the cells “ready to attack,” and significantly improved their ability to destroy tumor cells.

CAR-based therapies have already changed cancer treatment, especially for blood-related cancers. But while CAR-T cells have been widely studied, researchers are still trying to work out how to get the best performance from CAR-NK cells.

The new study focused on one of the main unanswered questions: which internal signaling mechanisms help these cells work at their best.

By building 2B4 and DAP12 into the CAR design, the team boosted the cells’ activation state. That made them more effective at targeting tumors, according to the study summary provided by Fundação de Amparo à Pesquisa do Estado de São Paulo, or FAPESP.

The researchers also tested a second approach, using a temporary drug-based control to fine-tune the cells.

They used dasatinib, a drug that can briefly suppress cell activity, to test how controlled pauses would affect performance. The results suggested that combining stronger activation signals with reversible pharmacological control improved the strength and efficiency of CAR-NK therapies.

According to the Ribeirão Preto Blood Center Press Office, experiments in animal models also produced encouraging results.

CAR-NK cells engineered with 2B4-DAP12 and pretreated with dasatinib controlled tumor growth better than more traditional versions of the therapy.

The work was carried out at the Center for Cell-Based Therapy, or CTC, which is one of the Research, Innovation, and Dissemination Centers supported by FAPESP. The CTC 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 of the University of São Paulo, or FMRP-USP.

The study adds to ongoing efforts to improve CAR-NK therapy design by identifying signaling domains that lift cell activity and by testing a drug-based method to temporarily suppress and then restore function.

The researchers said this combination could help in developing more advanced and controllable cell-based cancer treatments.

The journal paper is titled 2B4 co-stimulation and dasatinib modulation enhance anti-CD19 CAR-NK-92 cell cytotoxicity. Its authors are Matheus Henrique dos Santos, Júlia Teixeira Cottas de Azevedo, Mara Elisama da Silva Januário, Dayane de Fátima Schmidt, Mariane Cariati Tirapelle, Alison Felipe Bordini Biggi, Sima Ebrahimabadi, Renata Nacasaki Silvestre, Dimas Tadeu Covas, Rodrigo T. Calado, and Virgínia Picanço-Castro.

It was published in Frontiers in Immunology in 2025, volume 16, with the DOI 10.3389/fimmu.2025.1675877.