The immune contexture plays a key role in response to immunotherapies and is tightly regulated by immune-intrinsic factors. However, tumor cell-intrinsic features also impact the immune fitness. Although melanoma has a high response rate to immunotherapies, half of patients show primary or acquired resistance. Melanoma is characterized by an exacerbated tumor cell plasticity regulated by Transcription Factors of the Epithelial-to-Mesenchymal Transition (EMT-TFs), and associated with tumor progression and resistance to targeted therapy. However, whether melanoma plasticity regulates the response to immunotherapy remains to be elucidated. Our previous results showed that the EMT-TF ZEB1 is associated with CD8 T cell exclusion by rewiring CXCL10 expression in melanoma cells and ZEB1 loss-of-function can sensitize anti-PD1-resistant melanoma mouse models (Plaschka et al., JITC, 2022). To follow up, we are investigating the impact of melanoma plasticity on i) other tumor-infiltrating immune cells and ii) response to immunotherapy. First, we developed multiplexed-immunofluorescence (multi-IF) panels to analyze macrophages and Dendritic Cell (DC) subsets, alongside with melanoma cell state. Analysis of cutaneous melanoma lesions from patients treated with curative (n=40) or adjuvant (n=60) immunotherapy revealed that ZEB1 is also associated with increased infiltration of immunosuppressive tumor-associated macrophages, and a high score of melanoma de-differentiation correlates with resistance to immunotherapy. Finally, we uncovered that aggregates of specific DC subsets are also associated with response to immunotherapy in melanoma patients. Underlying signaling pathways and soluble mediators regulating the crosstalk between melanoma cell plasticity and macrophages or DC subsets are currently under investigation. Overall, we evidence melanoma phenotype plasticity as a driver of immune escape, which can be targeted to overcome resistance to immunotherapy. We also propose to develop and evaluate the power of a composite score including tumor-intrinsic plasticity markers alongside with immune parameters to better predict patients’ response to immunotherapy in melanoma.