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Theranostics 2024; 14(6):2605-2621. doi:10.7150/thno.92672 This issue Cite

Research Paper

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

Sri Murugan Poongkavithai Vadevoo^1,2,3,*, Yeoul Kang^4,*, Gowri Rangaswamy Gunassekaran^1,2,3, Seok-Min Lee^1,2,3, Min-Sung Park^1,2,3, Dong Gyun Jo^1,2,3, Sang-Kyun Kim⁵, Ho Lee⁶, Won Jong Kim^4,✉, Byungheon Lee^1,2,3,✉

1. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
2. Department of Biomedical Science, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
3. CMRI, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea.
4. Department of Chemistry, POSTECH-CATHOLIC Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea.
5. Laboratory Animal Center, K-Medi Hub, 88 Dongnae-ro, Dong-gu, Daegu 41061, Republic of Korea.
6. Laboratory Animal Research Facility, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Koyang, Kyunggi 10408, Republic of Korea.
* These authors equally contributed.

✉ Corresponding authors: Byungheon Lee, Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea. Phone: +82-53-420-4824, Fax: +82-53-422-1466, E-mail: leebhac.kr. Won Jong Kim, Department of Chemistry, POSTECH-CATHOLIC Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk 37673, Korea. Phone: +82-10-9426-2104, E-mail: wjkimac.kr. More

Abstract

Rationale: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: IL4 receptor, M2-macrophage, nab-paclitaxel, reprogramming, immunotherapy

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