Engineered Probiotics Remodel the Tumor Immune Microenvironment.

Abstract

Living treatments signify novel anticancer strategies employing living microorganisms with selective tropism to achieve effective therapeutic results. Nevertheless, the effective translation of bacterial biological products into clinical applications is still challenging, mainly because primitive microorganisms demonstrate limited therapeutic potential in tumor treatment. The hybridization of living bacteria with synthetic ingredients can provide diverse therapeutic functions to the targeted area, facilitating various interactions that offer exceptional therapeutic prospects compared to those of unhybridized living microbes. Here, αPD1 antibody-engineered <i>Lactobacillus rhamnosus</i> GG (LGG) is hybridized with sonopiezocatalytic BaTiO₃ nanoparticles (BTO NPs) for enhanced tumor-targeted accumulation and antitumor therapy. Targeted delivery of the system to tumor hypoxic regions utilizes the hypoxia affinity of LGG. Ultrasound irradiation of BTO NPs generates reactive oxygen species through a piezoelectric catalytic reaction, which induces immunogenic cell death (ICD) of tumor cells. The accompanied oxygen production during the piezoelectric catalysis mitigates tumor hypoxia, working in conjunction with probiotics to enhance significant and sustained antitumor immune activation, thereby augmenting the efficacy of immune checkpoint blockade (ICB) therapy. This study proposes an engineered and hybridized microbial-based tumor immunotherapy approach for selective and ultrasound-controllable tumor catalytic therapy.