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.