Harnessing the cGAS-STING-IFN-λ signaling to reprogram the immunosuppressive niche of Multiple Myeloma and potentiate NK cell–mediated tumor control

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS–STING) pathway is a central component of anti-tumor innate immunity, yet its downstream mediators and functional impact in multiple myeloma (MM) remain poorly characterized. Here, we identify type III interferons (IFNλs) as the dominant cytokines induced by STING activation in MM cells. Treatment with the STING agonist diABZI triggered robust activation of the STING-TBK1-IRF3 axis and selective upregulation of IFNλ1 transcripts and protein in both established MM cell lines and primary malignant plasma cells, whereas type I IFN induction was minimal. Stabilization of STING signaling through the ubiquitination inhibitor TAK-243 further enhanced IFNλ1 expression. Functionally, IFNλ1 inhibited MM cell proliferation and induced apoptotic cell death in an IFNLR1-dependent manner, underscoring a direct anti-tumor role. Moreover, diABZI and IFNλ1 promoted CD38 upregulation on MM cells, enhancing daratumumab (DARA)-mediated antibody-dependent cellular cytotoxicity (ADCC) by NK cells. Notably, combination of diABZI with the proteasome inhibitor bortezomib synergistically amplified IFNλ1 production, interferon-stimulated gene (ISG) expression, and cell death. Similarly, IFNλ1 cooperated with sublethal doses of bortezomib to potentiate caspase-3 activation and interferon-driven transcriptional programs. These findings define IFNλ1 as a key downstream effector of STING signaling in MM and unveil its dual role in directly suppressing tumor cell survival and enhancing immune-mediated cytotoxicity. Our data provide mechanistic and translational rationale for therapeutic strategies combining STING agonists, IFNλ1, bortezomib, and DARA to reinforce myeloma immunosurveillance and overcome resistance.