Cancer immunotherapy based on chimeric antigen receptor (CAR)-engineered T-cells represents a highly efficient therapy and a paradigm shift as living drugs. This platform allows further improvement of therapeutic cells and circuits that guide them. T-FITNESS project addressed the problem of T cell exhaustion aiming to enable antitumor T cells to become refractory to exhaustion. T-FITNESS proposed an innovative sensing of exhaustion-specific miRNAs (ex-miRNA) and transcription factors (exTF) to introduce downregulation of exTF by CRISPR-mediated genomic integration of miRNA target sites and also included the development of a cGMP-compliant manufacturing process. T-FITNESS-HOP-ON aims to achieve the same goal by introducing additional strategies based on protein design and synthetic biology tools. Here inhibitory TFs will be designed to prevent T cell exhaustion where they will be regulated either by external signals or through an autonomous ex-miRNA regulation. An innovative, single-transcript sensing of ex-miRNA and TFinh upregulation will be implemented. Additionally, CAR constructs will be designed to enable the rest of T-cells upon the onset of exhaustion and tested in T-cells and in a preclinical model. The proposed designs have a small genetic footprint and will not require genome editing, which could enable robust clinical translation and could be useful as a technological platform for therapy of other types of disease. The introduction of an additional widening partner, who brings new expertise and ideas will be beneficial both for the existing consortium as well as for the new partner, to improve dissemination, visibility, scientific excellence, facilitate clinical and industrial translation, strengthen the links with international partners and improve career prospects.