Furthermore, mechanisms whose functional regulation is mediated by the E-box transcription factors TCF4 and BRD4, the transcriptional and epigenetic regulators, such as the cytoprotective enzyme heme oxygenase-1 (HO-1), the loss of Kelch-like ECH-associated protein 1 (KEAP1) and the loss of E-cadherin, are described as resistance-driving factors that can inhibit the blockades of immune checkpoints and subsequently trigger melanoma resistance to immunotherapy [234,235,236]. Here, HMOX1 is linked to melanoma.