XBP1‐MARCH5‐Mfn2 pathway increase resistance against ERS by cooperating mitochondrial dynamics and mitophagy in melanoma. Activation of the IRE1α/ATF6‐XBP1 pathway promotes MARCH5 transcription and MFN2 degradation, activating mitochondrial fission and mitophagy. Here, ERN1 is linked to melanoma.