MicroRNA-induced reprogramming of tumor-associated macrophages for modulation of tumor immune microenvironment

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and typically exhibit pro- tumoral phenotypes. TAMs overexpress the signal regulatory protein alpha (SIRP alpha) receptor on their surface, which interacts with CD47 on tumor cells to inhibit their phagocytic activity. In this study, we developed lipid nanoparticles modified with an anti-SIRP alpha antibody (aSIRP alpha) for the targeted delivery of microRNA-155 (miR155@aSIRP alpha-LNP) to TAMs, aiming to enhance their anti-tumoral phenotypes within the tumor microenvironment. The aSIRP alpha modification not only facilitated nanoparticle uptake by TAMs rather than B16F10 cells, but also blocked the anti-phagocytosis signal by disrupting the interaction between SIRP alpha and CD47 on cancer cells. This dual functionality enhanced the expression of anti-tumoral phenotype markers in TAMs and activated macrophage-mediated phagocytosis of tumor cells. In a melanoma model, intratumoral administration of miR155@aSIRP alpha-LNP to B16F10 tumor-bearing mice reprogrammed TAMs toward anti-tumoral phenotypes. The anti-tumoral cytokines released by these TAMs remodeled the immunosuppressive tumor microenvironment, increasing cytotoxic T cell infiltration and reducing the regulatory T cell population, inhibiting tumor progression. This approach indicates the potential of miRNA-based therapies to overcome the limitations of current immunotherapies in treating cold solid tumors. Overall, the results suggest that delivering miR155 to TAMs by targeting SIRP alpha is a promising strategy for modulating the immunosuppressive tumor microenvironment in cancer immunotherapy.