Tumor microenvironment remodeling via targeted depletion of M2-like tumor-associated macrophages for cancer immunotherapy.

M2-like tumor-associated macrophages (TAMs) typically exhibit numerous tumor-promoting properties. Reducing the abundance of M2-like TAMs would shed light on the relief of immunosuppressive tumor microenvironment (TME), activation of the host immune system, infiltration of CD8 T cells into the TME and restoring the function of the infiltrating T cells, which collectively inhibits tumor growth. Therefore, targeted depletion of M2-like TAMs can be a promising immunotherapy approach. In this study, we rationally constructed an M2-like TAMs-targeted nanoliposome, which encapsulates zoledronic acid (ZA) in the core, loads hematoporphyrin monomethyl ether (HMME, a typical sonosensitizer) in the lipid bilayer, and modifies M2pep peptide (the targeting unit) on the surface (designated as M-H@lip-ZA). Our aim is to validate the effectiveness of M-H@lip-ZA nanoliposomes to remodel TME via targeted depletion of M2-like TAMs for cancer immunotherapy. Through the M2pep peptide, M-H@lip-ZA can be efficiently delivered to M2-like TAMs. In the meantime, reactive oxygen species (ROS) resulting from sonodynamic therapy (SDT), together with inner ZA that shows high affinity and cytotoxicity to TAMs, can effectively deplete M2-like TAMs and remodel TME (normalize tumor vasculatures, strengthen intertumoral perfusion, ease tumor hypoxia, increase immune-promoting cytokines and decrease immunosuppressive cytokines). The tumor growth can be effectively inhibited. This work proposed a new paradigm for cancer immunotherapy via targeted depletion of M2-like TAMs. STATEMENT OF SIGNIFICANCE: • M2-like TAMs-targeted nanoliposome (M-H@lip-ZA) was designed and prepared. • Sonodynamic therapy (SDT), together with zoledronic acid (ZA) that shows high affinity and cytotoxicity to tumor-associated macrophages (TAMs), can effectively deplete M2-like TAMs. Subsequently, immune-promoting tumor microenvironment (TME) can be formed, which includes normalized tumor vasculatures, enhanced intertumoral perfusion, relieved tumor hypoxia, increased immune-promoting cytokines, and decreased immunosuppressive cytokines. • The targeted depletion of M2-like TAMs is a promising cancer immunotherapy approach.