IL4 receptor targeting enables nab-paclitaxel to enhance reprogramming of M2-type macrophages into M1-like phenotype via ROS-HMGB1-TLR4 axis and inhibition of tumor growth and metastasis

• Published in: Theranostics 2024-01, Vol.14 (6), p.2605-2621
• Main Authors: Vadevoo, Sri Murugan Poongkavithai, Kang, Yeoul, Gunassekaran, Gowri Rangaswamy, Lee, Seok-Min, Park, Min-Sung, Jo, Dong Gyun, Kim, Sang-Kyun, Lee, Ho, Kim, Won Jong, Lee, Byungheon
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; Animals; Cell Line, Tumor; Female; HMGB1 Protein - metabolism; Humans; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Paclitaxel - pharmacology; Phenotype; Reactive Oxygen Species - metabolism; Receptors, Interleukin-4 - metabolism; Research Paper; Signal Transduction - drug effects; Toll-Like Receptor 4 - metabolism
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.92672

Nab-paclitaxel (Abx) is widely employed in malignant tumor therapy. In tumor cells and pro-tumoral M2-type macrophages, the IL4 receptor (IL4R) is upregulated. This study aimed to elucidate the selective delivery of Abx to M2-type macrophages by targeting IL4R and reprogramming them into an anti-tumoral M1-type. Abx was conjugated with the IL4R-binding IL4RPep-1 peptide using click chemistry (IL4R-Abx). Cellular internalization, macrophage reprogramming and signal pathways, and tumor growth and metastasis by IL4R-Abx were examined. IL4R-Abx was internalized into M2 macrophages more efficiently compared to the unmodified Abx and control peptide-conjugated Abx (Ctrl-Abx), which was primarily inhibited using an anti-IL4R antibody and a receptor-mediated endocytosis inhibitor compared with a macropinocytosis inhibitor. IL4R-Abx reprogrammed the M2-type macrophages into M1-like phenotype and increased reactive oxygen species (ROS) levels and extracellular release of high mobility group box 1 (HMGB1) in M2 macrophages at higher levels than Abx and Ctrl-Abx. The conditioned medium of IL4R-Abx-treated M2 macrophages skewed M2 macrophages into the M1-like phenotype, in which an anti-HMGB1 antibody and a toll-like receptor 4 (TLR4) inhibitor induced a blockade. IL4R-Abx accumulated at tumors, heightened immune-stimulatory cells while reducing immune-suppressing cells, and hampered tumor growth and metastasis in mice more efficiently than Abx and Ctrl-Abx These results indicate that IL4R-targeting allows enhancement of M2-macrophage shaping into M1-like phenotype by Abx through the ROS-HMGB1-TLR4 axis, improvement of antitumor immunity, and thereby inhibition of tumor growth and metastasis, presenting a new approach to cancer immunotherapy.