Issue 6, 2025

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

Abstract

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.

Graphical abstract: Reversing cancer immunosuppression via K+ capture and repolarization of tumor-associated macrophages

Supplementary files

Article information

Article type
Communication
Submitted
31 Jan 2025
Accepted
13 Mar 2025
First published
27 Mar 2025

Nanoscale Horiz., 2025,10, 1107-1119

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

S. Tong, C. Huo, Y. Zuo, S. Gao, D. T. Leong, W. Xue and J. Zhu, Nanoscale Horiz., 2025, 10, 1107 DOI: 10.1039/D5NH00050E

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