Melanoma is among the most aggressive skin cancers and accounts for the majority of cutaneous cancer-related mortality. The advent of immune checkpoint blockade (ICB) marked a major therapeutic breakthrough, restoring antitumor immunity by blocking inhibitory checkpoint pathways and reinvigorating exhausted T cells. Its clinical efficacy, however, critically depends on a pre-existing or inducible antitumor immune response, and a substantial proportion of patients therefore fail to respond or develop primary or acquired resistance. Immunologically "cold" tumors—characterized by limited cytotoxic T cell infiltration and impaired antigen presentation—are particularly refractory to ICB.

Melanoma cells are known for their pronounced phenotypic plasticity, which allows them to switch between cell states and thereby contributes to therapy resistance. Recently, a distinct melanoma subpopulation with an immune-like phenotype has been described, characterized by enhanced antigen presentation, increased T cell engagement, and strong interferon and stress-response signaling. This phenotype can be induced by introducing specific transcription factors into melanoma cells. Our own preliminary data point to PU.1 as a key candidate among these factors. Building on these findings, the present project investigates the role of endogenous PU.1 expression in driving the immune-like phenotype and elucidates its impact on antitumor immunity. By characterizing PU.1-dependent mechanisms and mapping its transcriptional network, we seek to establish a novel therapeutic axis for converting immunologically cold melanoma into tumors responsive to ICB.