An Engineered Probiotic Consortium Based on Quorum‐Sensing for Colorectal Cancer Immunotherapy

Abstract Recent progress in synthetic biology has empowered engineered probiotics to sense tumor‐specific physicochemical signals, thereby facilitating targeted in situ drug delivery. Here, an engineered probiotic consortium capable of integrating multiple tumor microenvironment (TME) signals and orchestrating multi‐therapeutic payloads release through an orthogonal quorum‐sensing system is designed. The probiotic consortium can respond to three characteristic TME parameters, pH, hypoxia, and high‐lactate levels, in order to achieve controlled release of lactate depletion enzyme (LdhA) for metabolic environment improvement and the programmed death ligand 1 (PD‐L1) nanobody for immune checkpoint inhibition. Using the humanized PD‐1 mouse model bearing hPD‐L1 MC38 tumor and the humanized peripheral blood mononuclear cells (PBMC) mouse model bearing HT‐29 tumor, it is demonstrated that this self‐regulating microbial consortium achieves sustained oscillations and significantly suppresses tumor progression. Mechanistic studies reveal that the antitumor efficacy activates CD8 + , CD4 + , and IFN‐γ + T cells, coupled with diminished immunosuppressive Foxp3 + regulatory T cell infiltration. This work advances the development of engineered live biotherapeutic products for cancer therapy and provides a modular platform for microbial consortium‐based precision medicine.