No abstract

The limited lymphocyte infiltration and exhaustion of tumoricidal functions in solid tumors remain a formidable obstacle to cancer immunotherapy. Herein, we designed a macrophage membrane-coated nano-gemcitabine system (MNGs) to promote lymphocyte infiltration and then synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes. MNGs exhibited effective intratumor-permeating and responsive drug-releasing capacity, produced notable elimination of versatile immunosuppressive cells, and promoted lymphocyte infiltration into cancer cell regions in tumors, but over 50% of these infiltrated lymphocytes were in the exhausted state. Compared with MNG monotherapy, the MNGs+antiPD-L1 combination produced 31.77% and 30.63% reduction of exhausted CD3 + CD8 + T cells and natural killer (NK) cells and 2.83-and 3.17-fold increases of interferon-γ (IFN-γ)-positive subtypes, respectively, thereby resulting in considerable therapeutic benefits in several tumor models. Thus, MNGs provide an encouraging strategy to promote lymphocyte infiltration and synergize antiPD-L1 to restore their tumoricidal function for cancer immunotherapy.

Tumor-associated macrophages (TAMs), one of the most important constituents in tumor immunosuppressive microenvironments, are a potential therapeutic target due to their essential role in promoting tumor progression and metastasis. Macrophages are usually divided into two categories of protumoral M2-like TAMs and antitumoral M1 phenotypes at the two extremes. Reprogramming M2-like TAMs toward tumoricidal M1 phenotype is especially intriguing in terms of the restoration of antitumor immunity for anticancer immunotherapy. In this review, the recent advances of nanomedicine-mediated reprogramming of TAMs from M2 to M1 to elicit the antitumor immunity are discussed. This reprogramming can be achieved via direct re-education by targeted delivery of various active agents to TAMs and indirect re-education by modulating the abnormal tumor microenvironment. Perspectives on nanomedicine mediated TAMs-M1 reprogramming for effective anticancer immunotherapy are also presented.