The clinical benefit of immune checkpoint inhibitory therapy (ICT) in advanced melanomas is limited by primary and acquired resistance. The molecular determinants of the resistance have been extensively studied, but these discoveries have not yet been translated into therapeutic benefits. As such, a paradigm shift in melanoma treatment, to surmount the therapeutic impasses linked to the resistance, is an important ongoing challenge.This review outlines the multifaceted interplay between microphthalmia-associated transcription factor (MITF), a major determinant of the biology of melanoma cells, and the immune system. In melanomas, MITF functions downstream oncogenic pathways and microenvironment stimuli that restrain the immune responses. We highlight how MITF, by controlling differentiation and genome integrity, may regulate melanoma-specific antigen expression by interfering with the endolysosomal pathway, KARS1, and antigen processing and presentation. MITF also modulates the expression of coinhibitory receptors, i.e., PD-L1 and HVEM, and the production of an inflammatory secretome, which directly affects the infiltration and/or activation of the immune cells.Furthermore, MITF is also a key determinant of melanoma cell plasticity and tumor heterogeneity, which are undoubtedly one of the major hurdles for an effective immunotherapy. Finally, we briefly discuss the role of MITF in kidney cancer, where it also plays a key role, and in immune cells, establishing MITF as a central mediator in the regulation of immune responses in melanoma and other cancers.We propose that a better understanding of MITF and immune system intersections could help in the tailoring of current ICT in melanomas and pave the way for clinical benefits and long-lasting responses.
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