Immunotherapies using tumor-fighting T cells, like TILs , or T cells engineered with specialized receptors (CAR or TCR), have been game-changers in cancer treatment. They have shown remarkable success in treating blood cancers like leukemia and lymphoma, but their efficacy against solid tumors has been underwhelming. A significant hurdle in making these therapies effective against solid tumors is what we call "T cell exhaustion”: during a protracted battle with tumor cells, T cells can become fatigued and are no longer able to function properly and to fight tumor cells efficiently. Our vision with T-FITNESS is to create exceptionally resilient T cells that can keep fighting and not get tired. To achieve this, we are developing molecular circuits that can lower the expression of the transcription factors (TFs) responsible for tiring out antitumor T cells. The challenge is that some of the TFs that make T cells exhausted are also important for their survival and effectiveness. Simply turning these TFs off completely is a bad idea because it would damage the T cells. Instead, we need to control these TFs very precisely to empower T cells to combat tumors effectively. Most current T-cell therapies use genetic tools to turn TFs on or off, but they can't control their expression very precisely. T-FITNESS sets itself apart by constructing a system that can adjust TF activity in T cells in a very fine-tuned way. We plan to use a genetic tool called CRISPR/Cas to insert synthetic "sensors" directly into well-defined sequences of the T cells’ DNA. These synthetic sensors are designed to detect specific signals, like a microRNA, that indicate when the T cells are becoming fatigued. As these sensors pick up these fatigue signals, they trigger precise adjustments in the T cell TFs to maintain their strength and effectiveness in the battle against cancer. T-FITNESS will seamlessly integrate into CAR-T, TCR-T, and TIL platforms, thereby unleashing the curative potential of T-cell therapy for an ever-growing number of cancer patients. This is particularly significant in Europe, where the number of new cancer cases per year is estimated to rise to 3.5 million by 2040.