A Nano “Immune‐Guide” Recruiting Lymphocytes and Modulating the Ratio of Macrophages from Different Origins to Enhance Cancer Immunotherapy

Artificially modulating the type, density, and location of immune cells within the tumor microenvironment can suppress tumor growth and efficiently promote current immunotherapy. In this study, a magnetite nanoparticle-based "immune-guide" is developed by the functionalization of magnetite nanoparticles with hyaluronic acid (HA). HA, an extracellular matrix component, can target various CD44-overexpressing tumors and mediate the adhesion and migration of multiple types of immune cells. Thus, HA-functionalized magnetite nanoparticles (HA-PDA@Fe3O4) can highly efficiently accumulate in breast cancer and penetrate deep into the tumor parenchyma. Consequently, high intratumoral concentration of HA, serving as a "guidepost," can directly recruit lymphocytes and elicit more chemokine production through cascading amplification effects, turning the immune "cold" tumor into a "hot" one. More importantly, HA-PDA@Fe3O4 can effectively remodel the diversity, origin, and activation of tumor-associated macrophages by recruiting and activating infiltrating macrophages, while simultaneously reducing the M2-maintained tissue-resident macrophages. Thus, HA-PDA@Fe3O4 synergistically improves T cell- and macrophage-based immunotherapies as well as interferes with the formation of premetastatic niches in the lung. By redistributing the localization of HA in tumors by using magnetite nanoparticles, this study provides a unique strategy to modulate the tumor immune microenvironment and potentiate tumor immunotherapies by using biocompatible nanomaterials without any therapeutic drug.