A Bone Marrow-Targeted Nanomodulator as Histone Lactylation Inhibitor for Reversing Immune Tolerance of Multiple Myeloma (PRJCA048037)
The metabolic-epigenetic interaction between tumor cells and immune components in the bone marrow microenvironment (BMM) plays a key role in immune evasion and resistance in multiple myeloma (MM). We present NanoCURE, a Cu-based bioactive nanomaterial designed to target the glycolysis-lactate-lactylation axis and reprogram the immunosuppressive BMM. NanoCURE co-delivers lactate oxidase (LOx) and bortezomib (BTZ) via a Cu2+ -activated nanoassembly, enabling bone marrow-specific delivery through monocyte/macrophage pathways. It inhibits histone lactylation and suppresses the Akt/mTOR/c-Myc axis, thereby blocking glycolysis and depleting lactate. Furthermore, NanoCURE induces reactive oxygen species (ROS), leading to mitochondrial dysfunction and epigenetic alterations. This reprogramming enhances immune responses, remodels the BMM, and amplifies anti-tumor immunity in a mouse model of MM. Overall, NanoCURE represents a promising strategy to overcome immune resistance in MM by targeting metabolic and epigenetic pathways.