Engineering Chameleon Prodrug Nanovesicles to Increase Antigen Presentation and Inhibit PD‐L1 Expression for Circumventing Immune Resistance of Cancer

Abstract Immune evasion is the major obstacle for T‐cell‐based cancer immunotherapy. The insufficient expression of the tumor‐rejection antigen causes the intrinsic immune resistance and high expression of programmed death ligand 1 (PD‐L1) induced by interferon gamma (IFN‐γ), which accounts for the inducible immune resistance. To deal with both the intrinsic and inducible immune resistance of cancer, a multifunctional prodrug nanovesicle is sequentially developed. It is first sorted out that doxycycline (Doxy) efficiently inhibits autophagy of the tumor cells, and increases the surface level of major histocompatibility complex class I (MHC‐I). Then, chameleon‐inspired prodrug nanovesicles are engineered for tumor‐targeted delivery of Doxy. The prodrug nanovesicles integrating a sheddable poly(ethylene glycol) shell and CRGDK ligand are kept stable during blood circulation, while exposing the targeting ligand in the tumor, which significantly inhibits autophagy, elicits MHC‐I expression, increases tumor antigen presentation, recruits more tumor‐infiltrating T lymphocytes, and suppresses FN‐γ‐induced intratumoral PD‐L1 expression. After a proof of concept for overcoming intrinsic and inducible immune evasion, the prodrug nanovesicles are applied to validate the efficacy of cancer immunotherapy in two tumor‐bearing mouse models. This research thus provides a novel targeting strategy for reducing tumor immune resistance and potentiating tumor immunotherapy.