Dual‐Engineered Macrophage‐Microbe Encapsulation for Metastasis Immunotherapy

Abstract Lung metastases are the leading cause of death among cancer patients. The challenges of inefficient drug delivery, compounded by a robust immunosuppressive microenvironment, make effective treatment difficult. Here, an innovative dual‐engineered macrophage‐microbe encapsulation (Du‐EMME) therapy is developed that integrates modified macrophages and engineered antitumor bacteria. These engineered macrophages, termed R‐GEM cells, are designed to express RGD peptides on extracellular membranes, enhancing their tumor cell binding and intratumor enrichment. R‐GEM cells are cocultured with attenuated Salmonella typhimurium VNP20009, producing macrophage‐microbe encapsulation (R‐GEM/VNP cells). The intracellular bacteria maintain bioactivity for more than 24 h, and the bacteria released from R‐GEM/VNP cells within the tumor continue to exert bacteria‐mediated antitumor effects. This is further supported by macrophage‐based chemotaxis and camouflage, which enhance the intratumoral enrichment and biocompatibility of the bacteria. Additionally, R‐GEM cells loaded with IFNγ‐secreting strains (VNP‐IFNγ) form R‐GEM/VNP‐IFNγ cells. Treatment with these cells effectively halts lung metastatic tumor progression in three mouse models (breast cancer, melanoma, and colorectal cancer). R‐GEM/VNP‐IFNγ cells vigorously activate the tumor microenvironment, suppressing tumor‐promoting M2‐type macrophages, MDSCs, and Tregs, and enhancing tumor‐antagonizing M1‐type macrophages, mature DCs, and Teffs. Du‐EMME therapy offers a promising strategy for targeted and enhanced antitumor immunity in treating cancer metastases.