Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced
Shuxian Cai1, Ziyi Chen1, Yingjie Wang1
1MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350116, P. R. China.
Abstract:
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.
Insights
A novel nanodrug (MS NPs) combines metformin and SN38 to reduce PD-L1 expression, enhancing chemo-immunotherapy and inhibiting tumor metastasis with low toxicity. This approach offers a new perspective for developing novel immune checkpoint inhibitors.
Area of Science:
- Nanomedicine
- Cancer Immunotherapy
- Drug Delivery Systems
Background:
- Immune checkpoint proteins programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) binding impairs T-cell surveillance.
- Immune checkpoint inhibitors (ICIs) restore T-cell antitumor function but can be limited by intracellular PD-L1 expression and redistribution.
- Intracellular PD-L1 can hinder the therapeutic efficacy of antibody-based ICIs.
Purpose of the Study:
- To develop a nanodrug (MS NPs) that reduces PD-L1 expression and enhances antitumor effects.
- To investigate the potential of MS NPs in overcoming limitations of current ICIs.
- To explore a novel chemo-immunotherapy strategy using repurposed drugs.
Main Methods:
- Self-assembly of metformin (Met) and 7-ethyl-10-hydroxycamptothecin (SN38) into MS NPs via hydrogen bonds and electrostatic interactions.
- Characterization of MS NPs, validation of PD-L1 down-regulation, and in vitro therapeutic effects.
- In vivo chemo-immunotherapy, tumor metastasis inhibition, and toxicity assessments in mice.
Main Results:
- MS NPs directly reduced PD-L1 levels, unlike ICIs, thereby achieving immunotherapy.
- MS NPs demonstrated enhanced chemo-immunotherapy effects and inhibited tumor metastasis by remodeling the extracellular matrix and restoring immune surveillance.
- MS NPs showed no obvious toxicity in major organs and resulted in a high survival rate in treated mice.
Conclusions:
- Designed nanodrug MS NPs combine immunoadjuvant Met and anticancer agent SN38 for synergistic chemo-immunotherapy.
- MS NPs offer a potential breakthrough beyond antibody-based ICIs by directly reducing PD-L1.
- Repurposing existing drugs through nanodrug formulation presents a novel strategy for developing next-generation immune checkpoint inhibitors.
