The study identifies Tyrosinase-Related Protein 1 (TYRP1) as a promising target for CAR-T cell therapy in patients with cutaneous and rare melanoma subtypes that are unresponsive to immune checkpoint blockade (ICB). TYRP1 is primarily located intracellularly in melanosomes but can be trafficked to the cell surface via vesicular transport. The researchers developed a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression, showing antitumor activity in vitro and in vivo in murine and patient-derived melanoma models. The therapy was well-tolerated, with no systemic or off-tumor severe toxicities observed in an immunocompetent murine model. The efficacy and safety profile support the preparation of a phase I clinical trial. The study highlights the potential of targeting intracellular transmembrane proteins that reach the cell surface through the secretory pathway, providing a novel approach to identify targetable surface proteins for CAR-T cell therapy.The study identifies Tyrosinase-Related Protein 1 (TYRP1) as a promising target for CAR-T cell therapy in patients with cutaneous and rare melanoma subtypes that are unresponsive to immune checkpoint blockade (ICB). TYRP1 is primarily located intracellularly in melanosomes but can be trafficked to the cell surface via vesicular transport. The researchers developed a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression, showing antitumor activity in vitro and in vivo in murine and patient-derived melanoma models. The therapy was well-tolerated, with no systemic or off-tumor severe toxicities observed in an immunocompetent murine model. The efficacy and safety profile support the preparation of a phase I clinical trial. The study highlights the potential of targeting intracellular transmembrane proteins that reach the cell surface through the secretory pathway, providing a novel approach to identify targetable surface proteins for CAR-T cell therapy.