Genetically Engineered Bacteria‐Derived Hydrogel Orchestrates T Cell Spatial Dynamics for Triple‐Negative Breast Cancer Immunotherapy

Abstract Impaired spatial dynamics of T cells represent a major challenge to effective immunotherapy in triple‐negative breast cancer (TNBC). Here, a genetically engineered, bacteria‐derived hydrogel is presented that precisely orchestrates T cell activation, trafficking, and tumor cell engagement. This hydrogel is formed in situ from bacterial outer membrane vesicles (OMV) engineered to display TNBC‐specific antigen α‐lactalbumin, chemokine CXCL10, and CXCR4 ectodomain (CXCR4E). The α‐lactalbumin antigen within OMV is internalized by dendritic cells, promoting robust T cell activation and systemic mobilization. Upon exposure to matrix metalloproteinase‐2 in tumor, the hydrogel enables spatiotemporally controlled release of CXCL10 and CXCR4E, facilitating T cell infiltration and overcoming CXCL12‐mediated contact resistance. In vivo, this strategy establishes a durable immune niche, enhances anti‐tumor T cell responses, and achieves significant tumor suppression with long‐term immune memory. The findings demonstrate the potential of programmable, bacteria‐derived hydrogels as a versatile platform for overcoming immune barriers and advancing immunotherapy in TNBC.