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The binding between the immune checkpoints, programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1), compromises T-cell-mediated immune surveillance. Immune checkpoint therapy using immune checkpoint inhibitors (ICIs) to block PD-L1 on cancer cell membrane or PD-1 on activated T cell membrane can restore antitumor function of T cell. However, the intracellular expression of PD-L1 and its active redistribution to cancer cell membrane may impair the therapeutic benefits of ICIs. To address this issue, herein we develop a nanodrug (MS NPs) capable of reducing PD-L1 expression and enhancing antitumor effects. Methods: The nanodrug was self-assembled from immunoadjuvant metformin (Met, an old drug) and anticancer agent 7-ethyl-10-hydroxycamptothecin (SN38) via hydrogen bonds and electrostatic interactions. A series of experiments, including the characterization of MS NPs, the validation of MS NPs-mediated down-regulation of PD-L1 expression and in vitro therapeutic effect, the MS NPs-mediated in vivo chemo-immunotherapy and tumor metastasis inhibition were carried out. Results: Different from ICIs that conformationally block PD-L1 on cancer cell membrane, MS NPs directly reduced the PD-L1 level via metformin to achieve immunotherapy. Therefore, MS NPs showed enhanced chemo-immunotherapy effect than its counterparts. MS NPs were also effective in inhibiting tumor metastasis by remodeling the extracellular matrix and restoring immune surveillance. Additionally, no obvious toxicity was observed in major organs from MS NPs-treated mice and a high survival rate of mice was obtained after MS NPs treatment. Conclusion: We have designed nanodrug MS NPs by self-assembly of the immunoadjuvant Met and the anticancer agent SN38 for combined immunotherapy and chemotherapy. MS NPs might break the deadlock of antibody-based ICIs in immunotherapy, and repurposing old drug might provide a new perspective on the development of novel ICIs.

Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy