Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages.

Increased levels of tumor-associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme-activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g., CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g., neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin-activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment. We describe the first enzyme‐activatable chemokine conjugates for selective targeting of tumor‐associated macrophages in preclinical models of cancer. We demonstrate that this new chemical design is compatible with both fluorescent and therapeutic payloads, opening avenues in the preparation of future theranostic probes for immune cells in the tumor microenvironment.

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© 2022 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.

Déclaration de conflit d'intérêts

The authors declare no conflict of interest.