Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy. The small GTPase ARF6 is known to regulate endocytosis and recycling of plasma membrane proteins. Here the authors show that tumourintrinsic ARF6 promotes an immunosuppressive microenvironment that accelerates melanoma progression but that is vulnerable to immune checkpoint blockade, mechanistically linked to ARF6-dependent recycling of interferon-gamma receptors in tumour cells.