Nanoengineered Macrophages Armed with TLR7/8 Agonist Enhance Remodeling of Immunosuppressive Tumor Microenvironment

Abstract Although adoptive cell‐based therapy is illuminated as one of the promising approaches in cancer immunotherapy, it shows low antitumor efficacy because transferred cells adapt and alter toward a pro‐tumoral phenotype in response to the tumor's immunosuppressive milieu. Herein, nanoengineered macrophages anchored with functional liposome armed with cholesterol‐conjugated Toll‐like receptor 7/8 agonist (masked TLR7/8a, m7/8a) are generated to overcome the shortcomings of current macrophage‐based therapies and enhance the remodeling of the immunosuppressive tumor microenvironment (TME). The liposome‐anchored macrophages (LAMΦ‐m7/8a), are fabricated by anchoring dibenzocyclooctyne‐modified liposome(m7/8a) onto azido‐expressing macrophages via a bio‐orthogonal click reaction, are continuously invigorated due to the slow internalization of liposome(m7/8a) and sustained activation. LAMΦ‐m7/8a secreted ≈3 and 33‐fold more IL‐6 and TNF‐α than conventional M1–MΦ, maintained the M1 phenotype, and phagocytosed tumor cells for up to 48 h in vitro. Both intratumoral and intravenous injections of LAMΦ‐m7/8a induced effective antitumor efficacy when treated in combination with doxorubicin‐loaded liposomes in 4T1‐tumor bearing mice. It not only increases the infiltration of antigen‐specific CD8 + T cells secreting granzyme B, IFN‐γ, and TNF‐α within the TME, but also reduces myeloid‐derived suppressor cells. These results suggest that LAMΦ‐m7/8a may provide a suitable alternative to next‐generation cell‐based therapy platform.