Augment proteasome inhibitor efficacy activates CD8+ T cell-mediated antitumor immunity in breast cancer.

Although three proteasome inhibitors are used for liquid tumor treatment, their effectiveness against solid tumors remains inadequate. To address this issue, we employ a drug combination strategy and discover that ammonium tetrathiomolybdate (TM) and AMD3100 can sensitize solid cancer cell lines to proteasome inhibitors. Mechanistically, we find that TM and AMD3100 reduce proteasome activity by decreasing the protein level of PSMB5. This reduction occurs through the activation of the AMP-activated protein kinase (AMPK) pathway, which inhibits STAT3 phosphorylation. Notably, our in vivo studies reveal that drug combinations retard tumor growth dependent on CD8⁺ T cells. The combination of bortezomib with TM or AMD3100 induces cancer cell antigen presentation and the production of CCL5, which together stimulate the recruitment and generation of cytotoxic CD8⁺ T cells. This study identifies synergistic lethal pairs that enhance the effectiveness of bortezomib-centered therapy for breast cancer treatment in a way relied on intact immune system.