Bone marrow plasmacytoid dendritic cells (pDCs) in patients with multiple myeloma (MM) contribute to tumor growth, survival, drug resistance, and immune suppression. Understanding the molecular signaling interactions between tumor cells, pDCs, and immune cells is crucial for identifying novel therapeutic strategies to enhance anti-MM immunity. Using oligonucleotide arrays, we discovered that pDC-MM interactions upregulate the metabolic enzyme Alpha-Enolase (ENO1) in both pDCs and MM cells. Analysis of gene expression data from MM patients revealed that ENO1 expression is inversely correlated with overall survival. Protein expression analysis confirmed that ENO1 is present in both pDCs and MM cells, with coculture of pDCs and MM cells further increasing ENO1 expression in both cell types. In coculture models using patient-derived autologous pDC-T-NK-MM cells, we investigated whether targeting ENO1 could enhance anti-MM immunity. Biochemical inhibition of ENO1 with an ENO1 inhibitor (ENO1i) activated pDCs and increased MM-specific CD8+ cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity against autologous tumor cells. Combining ENO1i with anti-PD-L1 antibodies or the HDAC6 inhibitor ACY-241 further boosted MM-specific CD8+ CTL activity. Our preclinical data suggest that targeting ENO1, either alone or in combination with anti-PD-L1 antibodies or ACY-241, may offer a novel immune-based therapeutic approach to restore anti-MM immunity, enhance MM cytotoxicity, and improve patient outcomes.