Programmable-bacteria-macrophage backpacks for enhanced solid tumor therapy via mechanobiological interplay

Current adoptive cell-based immunotherapies have demonstrated limited efficacy against solid tumors, largely due to dynamic cellular phenotypic shifts and the immunosuppressive tumor microenvironment (TME). To address these challenges, we developed an ultrasound (US)-controlled bacteria-macrophage hybrid system, which employs genetically engineered bacteria designed to release chemokine CCL21 for immune cell recruitment. These bacteria are further surface-modified to enable bromelain conjugation and facilitate the formation of bacterial “backpacks” on macrophages. In vivo experiments confirmed that US activation of this system effectively promotes macrophage repolarization to the M1 phenotype within the TME and enhances immune cell infiltration. Moreover, the treatment significantly reduced collagen I deposition, which weakened the mechanobiological properties of tumor cells, thus mitigating tumor-mediated immune evasion. Collectively, the system remodels the immunosuppressive TME, facilitating increased infiltration of dendritic cells and CD4⁺/CD8⁺ T cells, and ultimately improving the outcomes of antitumor immunotherapy.