Overcoming proteasome inhibitor resistance in the immunotherapy era

Proteasome inhibitors (PIs) are a fascinating class of small molecules that disrupt protein homeostasis and are highly efficacious in the blood cancer multiple myeloma. However, PIs are not curative, and overcoming PI resistance to extend patient survival remains a major unmet need. Recent strategies to overcome PI resistance, including inhibiting alternative protein homeostasis pathways and targeting the mitochondrion as a nexus of metabolic adaptation to PIs, are gaining momentum. However, these focused approaches may be surpassed or even obviated by quickly emerging immunotherapy strategies that do not selectively target PI resistance mechanisms but are highly efficacious in PI-resistant disease, nonetheless. Informed by insights from these promising areas of research moving in parallel, we propose that pharmacological strategies to enforce immunotherapeutic vulnerabilities in resistant disease may provide a unified outlook to overcome PI resistance in a 'new era' of myeloma treatment.