On‐Demand Controlled Release Multi‐Drugs Delivery System for Spatiotemporally Synergizing Antitumor Immunotherapy

Abstract Although cytotoxic T lymphocytes (CTLs) activation combined with programmed cell death‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) axis blockade have emerged as an effective strategy to improve immunotherapeutic potency, it remains challenging to realize the spatiotemporal synergy of these two components. Herein, the study reports an engineered bacterial‐based delivery system that can simultaneously promote CTLs infiltration and control PD‐L1 binding protein (PD‐L1 trap) release on demand at tumor site. The drug release button of this tumor targeting system is the specific temperature, which is accomplished by dual‐modified melanin nanoparticles with photothermal conversion capacity on the engineered bacterial. These dual‐modified nanoparticles can form in situ reservoir of heat supplier and antitumor immunity activator once arriving at tumor microenvironment (TME). Importantly, the study establishes the personalized administration regimen according to TME changes, and perform local laser irradiation to trigger PD‐L1 trap production only in TME when infiltrated CTLs reach the highest level. This work provides a flexible platform for optimizing cancer immunotherapy.