Patient-derived T cells that carry chimeric antigen receptors (CARs) demonstrate remarkable clinical activity against malignancies of different origins. Aim of this DKTK project was the development of a versatile approach for cancer immunotherapy that bypasses the need for patient-individual cell products. Thereby, natural killer (NK) cells are employed as alternative effectors, which carry a universal CAR (UniCAR) and can be safely used in an allogeneic setting. The UniCAR is only activated in the presence of a so-called target module (TM), a soluble adapter which contains a tumor-specific binding domain and a peptide recognized by the UniCAR. This increases safety by allowing to tightly control duration and magnitude of CAR activation. Important results from this project bringing together nine research groups from four DKTK partner sites include the identification of suitable target structures most frequently presented on the surface of melanoma cells, the development of a novel design for TMs with increased half-life, and proof-of-concept for this strategy in preclinical tumor models. These data may aid the further development of this approach towards clinical application of UniCAR-NK cells as a novel therapy for melanoma.