Hypoxia-activated paclitaxel prodrugs enable PD-L1 degradation to potentiate cancer chemo-immunotherapy.

The combination of chemotherapy and immune checkpoint blockade therapy shows great potential in tumor treatment, but their integration remains a great challenge. Herein, hypoxia-responsive prodrugs integrating paclitaxel (PTX) and bromodomain-containing protein 4 inhibitor JQ1 were designed and fabricated into nanoparticles (DJNP NPs) in the presence of DSPE-PEG(2000). After accumulation at the tumor site, DJNP NPs can respond to tumor hypoxic condition and trigger the release of PTX and JQ1. The released PTX can result in cell apoptosis, which further evokes immunogenic cell death to boost the intratumoral infiltration of cytotoxic T lymphocytes. Meanwhile‌, overexpression of programmed cell death ligand 1 (PD-L1) is suppressed by JQ1, thereby reversing PD-L1-mediated immune resistance to synergistically promote adaptive antitumor immune response. This hypoxia-sensitive versatile nanoplatform provides an elegant paradigm for precise tumor therapy.