ClpP: a new Achilles' heel in myeloma Free

In this issue of Blood, Perini et al¹ have elegantly and clearly proven how the mitochondrial protease, caseinolytic peptidase (ClpP), presents a critical vulnerability in multiple myeloma (MM), where it functions both as a metabolic dependency and as a molecular switch for immune activation. These findings establish a new immunogenic chemotherapeutic framework with potential relevance for the treatment of MM.

Mitochondrial function has been demonstrated to be essential for cancer pathogenesis^2-4; however, its specific role in MM remains incompletely defined and largely unexploited as a novel therapeutic avenue. The authors have demonstrated that ClpP is markedly overexpressed in MM plasma cells compared with their normal counterpart cells and compared with plasma cells in premalignant conditions, including both monoclonal gammopathy of undetermined significance and smoldering MM. Moreover, MM cell lines were shown to present with the highest expression of ClpP among tested human cancers.

Although ClpP has been previously implicated in maintaining mitochondrial proteostasis,^5,6 its pivotal role in MM biology appears to be uncoupled from classical oxidative phosphorylation. Instead, it regulates a specific metabolic axis centered on ornithine aminotransferase, which supports the biosynthesis of polyamines---key players in sustaining MM cell proliferation.

Strikingly, halting ClpP not only results in direct MM cytotoxicity, as demonstrated both in vitro and in vivo, but also unleashes a potent immunogenic response. ClpP-silenced cells activate the cGAS-STING pathway, leading to a robust type I interferon signature that primes dendritic cells and enhances T-cell–mediated immunity. In immunocompetent mouse models, this translates into a restructured bone marrow immune microenvironment, characterized by expanded populations of interferon-γ–producing CD4⁺ and CD8⁺ T cells and memory T cells, alongside a reduction in exhausted T cells and immunosuppressive myeloid-derived suppressor cells. These findings suggest that ClpP inhibition effectively remolds the typically immunologically quiescent myeloma niche into an immunoreactive state.

Thus, this study positions ClpP as more than a metabolic safeguard: it emerges as a crucial node at the intersection of tumor metabolism and innate immunity. The therapeutic implications are significant, showing that targeting ClpP may offer a dual benefit by inducing direct MM cell death and awakening antitumor immunity, potentially enhancing the efficacy of immune-based therapies. As the field moves toward integrating metabolic and immunological interventions, ClpP may represent a novel and compelling therapeutic target with the potential to reshape the treatment landscape of MM.

What should happen next? Certainly, further studies are needed to better dissect the potential transcriptional and epigenetic circuits responsible for the upregulation of ClpP in MM cells. Furthermore, clarifying the role of ClpP within the context of MM disease initiation, clonal expansion, or dissemination could reveal new biological dependencies that emerge during tumor evolution. Ultimately, unraveling the broader regulatory landscape of ClpP could not only deepen our mechanistic understanding of myeloma biology but also enhance the strategic deployment of ClpP-directed therapies, either as monotherapy or in combination with immune-based approaches.

Conflict-of-interest disclosure: A.S. has received research funding from Associazione Italiana Contro Leucemie, Linfoma e Mieloma (AIL Brescia). A.M.R. has received research funding from Associazione Italiana per la Ricerca sul Cancro (Fondazione AIRC), Associazione Italiana contro Leucemie, Linfoma e Mieloma (AIL Brescia), AstraZeneca, the European Hematology Association, Fondazione Regionale per la Ricerca Biomedica, Transcan2-ERANET, the International Waldenstrom’s Macrogobulinemia Foundation, and the Leukemia & Lymphoma Society and honoraria from AbbVie, Amgen, Beigene, Celgene, Janssen, Roche, and Takeda.