Reprogrammed Lung Metastasis Immunodeficiency via Targeted Penetrated Delivery of M1 Macrophage‐Wrapped NanoCubes‐Mediated T Cell Infiltration

Abstract The infiltration of cytotoxic T lymphocytes holds promise for suppressing even the most resilient metastatic tumors in immunotherapy. Polarizing tumor‐associated macrophages (TAMs) and remodeling the immune‐deficient tumor microenvironment (TME) can enhance T lymphocyte recruitment and infiltration. However, the immune privilege and low immunogenic responses of these aggressive tumor clusters often limit lymphocyte recruitment. Here, an M1 macrophage membrane‐coated iron oxide nanoparticle (IO@MM) double as a tumor‐penetrated agent and naïve M0 macrophage to M1 polarizer is developed for lung metastatic colorectal cancer (CRC) immunotherapy. At the tumor site, IO@MM combined with resiquimod (R848) increased the immune cell infiltration, turning the “Cold” TME into an immune‐activating “Hot” one. Together with self‐cascade immunotherapy, IO@MM with R848 promotes tumor release of damage‐associated molecular patterns (DAMPs). At the same time, IO@MM uses the membrane as an antigen reservoir and provides autologous DAMPs to retain dendritic cells. This IO@MM effectively inhibits tumors and improves survival rate as an immunomodulator in lung metastasis.