STAT3 inhibition eradicates multiple myeloma stem-like cells and induces immunogenic cell death

Signal transducer and activator of transcription 3 (STAT3) is a pivotal oncogenic driver in multiple myeloma (MM), and its constitutive activation promotes malignant plasma cell proliferation, survival, and drug resistance in the bone marrow microenvironment. Despite therapeutic advances, MM remains incurable due to persistent STAT3-driven tumorigenesis and the resilience of MM stem cells. We investigated the therapeutic potential of napabucasin (BBI608), a novel STAT3 inhibitor, in MM. Our data demonstrated that BBI608 potently suppressed MM cell proliferation in vitro and in vivo, while significantly impairing the clonogenic potential and inducing robust apoptosis. Mechanistically, BBI608 exhibited dual efficacy by targeting bulk tumor cells and eradicating the stem-like compartment of MM cells, thereby addressing a critical therapeutic challenge. Moreover, we revealed that BBI608 triggered immunogenic cell death (ICD) via the activation of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which subsequently enhanced T-cell–mediated anti-tumor immunity. Our findings highlight STAT3 inhibition as a promising strategy to simultaneously eradicate MM cells, target stem cell reservoirs, and harness anti-tumor immunity, providing a robust rationale for the clinical translation of BBI608 in MM therapy.