The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma.

Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, because of their bacterial ancestry, they can release potent immunogenic signals. In this study, we showed that the mitochondrial protease caseinolytic peptidase P (ClpP) is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP messenger RNA is higher in bone marrow (BM)-purified malignant plasma cells than in normal or premalignant counterparts and that MM lines rank first in ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, which are essential for MM cells. Transcriptomics and targeted validation also revealed the activation of a cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFN-γ production by T cells. In vivo, ClpP silencing reshaped the BM immune environment in immunocompetent mice by significantly expanding IFN-γ-producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid-derived suppressor cells. Thus, ClpP is a newly identified addiction of MM cells whose inhibition not only exerts cell-intrinsic toxicity but also triggers otherwise indolent antitumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework with potential relevance to myeloma.