Development of bacterial sonosensitizer hybrid systems to enhance cancer sono-immunotherapy

Microorganisms can activate anti-tumor immune responses via the innate immune system. However, this immune effect lacks specificity, and prolonged stimulation by live bacterial colonization may lead to immune tolerance. Sonodynamic therapy triggers cellular death and lysis, fully activating the antigen presentation process by providing heterologous DNA and tumor antigen in situ. Herein, to enhance the immunological effect facilitated by ultrasonic treatment, a manganese-containing porphyrin-based metal-organic framework (Mn-MOF) was modified as an acoustic sensitizer on the surface of Escherichia coli to form bacterial sonosensitizer hybrid systems (HA@Mn-MOF@E). Importantly, HA@Mn-MOF@E was able to target and colonize 4T1 tumors due to the anoxic tendency of anaerobes. The ultrasound-induced bacterial and tumor cell death and released manganese could activate macrophages and dendritic cells (DCs) through the activation of the cGAS-STING pathway, which increased the proportion of CD3⁺ T cells and M1/M2 ratio within the tumor, as well as CD8⁺ effector T cells and CD86⁺ DCs in lymph nodes. By sono-sensitized immunotherapy, HA@Mn-MOF@E was demonstrated to inhibit orthotopic 4T1 tumor progression and induce tumor necrosis effectively. Such a designed bacterial sonosensitizer hybrid system offered the possibility of using sonodynamic assistance to sensitize live microorganisms-induced immunotherapy, with thorough activation of the antigen presentation in the tumor.