Reversing cancer immunosuppression via K+ capture and repolarization of tumor-associated macrophages†

Immunosuppression from the tumor microenvironment plays a key role in the failure of cancer immunotherapy. The presence of potassium ions (K⁺) from dying tumor cells creates an immunosuppressive environment that encourages tumor-associated macrophages (TAMs) to adopt a pro-tumor M2-like phenotype. Alleviating immune suppression from the high K⁺ environment might boost innate immunity and fight tumor growth. Herein, disulfide-rich mesoporous silica modified with 18-crown-6 ether was developed as a nanocarrier (D-C) to load ML133, encapsulating with the DiR-embedded macrophage membrane (CM) to create D-C/M@CM/DiR. We first saturated the phagocytosis of the mononuclear phagocyte system (MPS) with blank nanocarriers to enhance the tumor accumulation of D-C/M@CM/DiR, which was coated with the same CM. 18-Crown-6 ether captures K⁺ to reduce immunosuppression, while ML133 promotes the polarization of TAMs to an anti-tumor M1 phenotype by targeting the K⁺ channel protein Kir2.1 on their membranes. This strategy activates the anti-tumor immune response and effectively inhibits tumor growth.