Melanoma cases and deaths are expected to increase in the coming years, representing a significant burden for the European economy and healthcare system. Metastatic melanoma (MM) is the most serious form of skin cancer and is characterised by uncontrolled metastatic spread of melanocytes to distant sites. Although standard treatments exist, significant clinical challenges remain, resulting in limited response and high MM recurrence rates. As a result of these limited treatment options, the quality of life of MM patients is dramatically compromised. Emerging immunotherapies, such as adoptive cell therapy (ACT), are promising but have significant obstacles, including long manufacturing times, high costs and, most critically, rapid exhaustion of infused cells due to the tumour immune microenvironment (TIME). Research in Gottfried Baier's lab has identified a unique way to effectively stimulate the immune system with an ACT by inhibiting NR2F6, an intrinsic immune checkpoint of T lymphocytes. This is done through our NR2F6 blockade-based adoptive immune cell therapy for metastatic melanoma (NR2F6-AIM) approach, where T cells are engineered for enhanced immune fitness prior to infusion. This greatly sensitises the patient's immune system to currently available immune checkpoint inhibitor therapy (ICT). This approach will permit us to deliver a combinatorial treatment that can overcome TIME immunosuppression, providing curative potential against MM. NR2F6-AIM will block NR2F6 by a non-viral, time-boxed gene silencing through a synthetic small interfering RNA (siRNA) transfection method. This method will allow us to overcome therapeutic manufacturing hurdles through a one-day in-hospital preparation of the ACT. NR2F6-AIM will verify and optimise the technology in relevant in vivo and ex vivo study models to validate the potential of this innovative ACT. It will also develop and execute an IP strategy and a commercial feasibility analysis to enter the MM market.