We demonstrated that 2DG and LLOMe synergistically induce severe energy depletion and mixed apoptotic–necrotic death of A375 melanoma cells by inhibiting both glycolysis and oxidative phosphorylation (OXPHOS), with 2DG primarily targeting glycolysis, while LLOMe predominantly impairs OXPHOS through LMP-induced cathepsin release and subsequent mitochondrial dysfunction. Here, CTSS is linked to melanoma.