Microenvironmental Snail1 is a driver of immunosuppression in melanoma

Melanoma is an aggressive form of skin cancer due to its high metastatic abilities and resistance to therapies. Melanoma cells reside in a heterogeneous tumour microenvironment that acts as a crucial regulator of its progression. Snail1 is an epithelial-to-mesenchymal transition transcription factor expressed during development and reactivated in pathological situations including fibrosis and cancer. In this work, we show that Snail1 is activated in the melanoma microenvironment, particularly in fibroblasts. Analysis of murine models that allow stromal Snail1 depletion and therapeutic Snail1 blockade indicate that targeting Snail1 activation in the tumour microenvironment decreases melanoma growth and lung metastatic burden, extending mice survival. Transcriptomic analysis of melanoma-associated fibroblasts and analysis of the tumours indicate that stromal Snail1 induces melanoma growth by promoting an immunosuppressive microenvironment and pro-tumour immunity. This study unveils a novel role of Snail1 in melanoma biology and supports its potential as a therapeutic target.