Assuming that changes of the immune niche by tumor-intrinsically elevated E2F1 expression could be mechanistically crucial for its prometastatic function, which also impairs the virtue of immunotherapies, the influence of this TF on the communication between highly aggressive melanoma and healthy donor-derived T cells was comprehensively investigated by an integrative approach combining cell coculture models, high-throughput analyses, and structure-based modeling. Here, E2F1 is linked to melanoma.