Modulation of M1 macrophage polarization by Fe₃O₄@Cu_2-xS engineering for improved tumor immunotherapy and MRI

Tumor-associated macrophage (TAM)-mediated immunotherapy holds significant potential for cancer treatment. However, the presence of M2-like TAMs significantly hinders the efficacy of therapeutic interventions, making the reprogramming of M2 macrophages into the pro-inflammatory M1 phenotype critical. In this study, we proposed core-shell structured Fe₃O₄@Cu_2-xS nanomaterials to engineer macrophages for enhanced tumor immunotherapy. Fe₃O₄@Cu_2-xS-engineered M1 macrophages (Fe₃O₄@Cu_2-xS@M1) could home to the tumor site and sustain their M1 phenotype within the tumor microenvironment (TME) while releasing NO, tumor necrosis factor-α (TNF-α), and other pro-inflammatory cytokines. A series of experimental results demonstrated that Fe₃O₄@Cu_2-xS@M1 could not only facilitate the conversion of the neighbor Mø and M2 macrophages to the M1 phenotype in the TME which could not be realized by unengineered M1 macrophages, but also maintain the M1 macrophage state for a longer time thanks to the multiple pathways regulation, thereby activating antitumor immunity and inhibiting tumor progression better. The enhanced MRI contrast performance of Fe₃O₄@Cu_2-xS facilitated non-invasive visualization of macrophage-driven immunotherapeutic processes in vivo. This study provided valuable insights into the use of nanomaterials with intrinsic immunomodulatory properties for effective cancer treatment.