Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin ( MTDH ) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH–SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH–SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH–SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.