Targeting metabolic reprogramming and epigenetic remodeling: a novel strategy to reshape the immune microenvironment...

Multiple myeloma (MM) is a highly debilitating hematologic malignancy with a significant risk of mortality, now entering an era of comprehensive treatment. However, immune resistance remains the primary obstacle limiting long-term survival and effective treatment in patients. Two critical tumor characteristics-metabolic remodeling and epigenetic reprogramming-interact to drive this process. Metabolic alterations induce epigenetic modifications, while epigenetic regulation reciprocally reshapes metabolic networks. These processes are tightly coupled, jointly shaping the tumor-immune microenvironment within the bone marrow and promoting immune evasion. Based on this understanding, targeting metabolic-epigenetic crosstalk may provide a conceptual framework for developing rational combination strategies. Rather than representing an established clinical approach, this framework may help identify mechanisms that restore antigen presentation, improve effector T- and NK-cell activity, and enhance the sensitivity of MM to immune-based therapies in selected molecular contexts. It may also provide a mechanistic basis for immunotherapy sensitization. This review describes how metabolic remodeling and epigenetic reprogramming interact in MM, how these interactions contribute to immune suppression, and their implications for developing improved combination therapies.