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

Although three proteasome inhibitors have been used for liquid tumor treatment, their effectiveness against solid tumors remains inadequate. To address this issue, we employed a drug combination strategy and discovered that ammonium tetrathiomolybdate (TM) and AMD3100 can sensitize solid cancer cell lines to proteasome inhibitors. Mechanistically, we found that TM and AMD3100 reduce proteasome activity by decreasing the protein level of PSMB5. This reduction occurs through the activation of the AMPK pathway, which inhibits STAT3 phosphorylation. Notably, our in vivo studies revealed that drug combinations retarded tumor growth dependent on CD8+ T cells. The combination of bortezomib with TM or AMD3100 induced cancer cell antigen presentation and the production of CCL5, which together stimulated the recruitment and generation of cytotoxic CD8+ T cells. This study identifies new synergistic lethal pairs that enhance the effectiveness of bortezomib-centered therapy against breast cancer. Overall design: HCC1937 cells treated with vehicle, 10µM TM or 10µM AMD3100 were collected for RNA-Seq. MDA-MB-231 cells treated with 10nM Bortezomib combined with 10µM TM or 10µM AMD3100 were collected for RNA-Seq. 4T1 tumor implanted into Balb/c mice were treated with 1mg/kg bortezomib every 4 days combined with 0.05mg/ml TM in drinking water or 5mg/kg AMD3100 every 2 days and collected for RNA-Seq.