Despite the unprecedented success of immune checkpoint inhibitors (ICI) in cancer therapy, one major unresolved dilemma is treatment resistance. Immunogenic cell death (ICD) constitutes a prominent pathway for the activation of anti-cancer immunity, which in turn determines the long-term success of anticancer therapies. Only a few agents can elicit bona fide ICD, including the proteasome inhibitor bortezomib, as demonstrated in malignant myeloma and mantle cell lymphoma, but not yet in melanoma. We show that bortezomib causes ICD in vitro through the induction of endoplasmic reticulum stress followed by autophagy, apoptosis and translocation/secretion of damage-associated molecular patterns (DAMPs). Moreover, vaccination with bortezomib-treated apoptotic melanoma cells induced tumour immunogenicity in vivo. Intralesional injection of bortezomib synergized with subsequent systemic treatment with ICI. Re-challenge demonstrated long-term protection through bortezomib combined with ICI. Polyfunctional T cell assays revealed that intralesional bortezomib injection generates a tumour-specific T cell response and was able to control secondary untreated tumours (abscopal effect). Importantly, ICI resistance was reverted by bortezomib-induced immunogenicity.