Immunogenic cell death (ICD) constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as the proteasome inhibitor bortezomib, as demonstrated in malignant myeloma and mantle cell lymphoma, but not yet in melanoma. We have shown in melanoma that bortezomib induces NOXA-dependent apoptosis. Here, we show that bortezomib indeed causes ICD in vitro through induction of endoplasmic reticulum stress, autophagy and apoptosis and through translocation and/or secretion of damage-associated molecular patterns (DAMPs). Vaccination with bortezomib-treated dead melanoma cells induced tumor immunogenicity in vivo, as evidenced in a significant reduction/delay after challenge with live cells. Intralesional injection of bortezomib synergized with subsequent systemic treatment with immune checkpoint inhibition using CTLA-4 and PD-1 antagonists. Re-challenge demonstrated long-term protection through bortezomib combined with immune checkpoint inhibition. Polyfunctional T cell assays revealed that intralesional bortezomib injection generates a tumor-specific T cell response. Finally, immune checkpoint inhibitor-resistance was reverted by bortezomib-induced immunogenicity. In summary, bortezomib induces ER stress and apoptosis, enhances ICD markers (DAMPs) in vitro and is immunogenic in vivo. Bortezomib-induced ICD is a good strategy to recruit the inflammatory immune response. Bortezomib-induced ICD enhances response to immune checkpoint inhibitors, even in ICI-resistant tumors. We propose intralesional injection of bortezomib combined with systemic CTLA-4 andPD-1 antagonists to improve immune therapy in melanoma.