Background: Among the many immunosuppressive cells in the tumor microenvironment, tumor-associated-macrophages (TAMs) are well known to contribute to
tumor development. TAMs can be conditioned (polarized) to transition between classical M1-like macrophages, or alternatively to M2-like macrophages. Both are regulated by signaling molecules in the microenvironment. M1-like TAMs can secrete classic inflammatory
cytokines that kill
tumors by promoting
tumor cell
necrosis and immune cell infiltration into the tumor microenvironment. In contrast, M2-like TAMs exhibit powerful
tumor-promoting functions, including degradation of
tumor extracellular matrix, destruction of basement membrane, promotion of angiogenesis, and recruitment of immunosuppressor cells, all of which further promote
tumor progression and distal
metastasis. Therefore, remodeling the tumor microenvironment by reversing the TAM phenotype will be favorable for
tumor therapy, especially
immunotherapy. Methods: PLGA nanoparticles encapsulating
baicalin and
melanoma antigen Hgp
peptide fragment 25-33 were fabricated using the ultrasonic double-
emulsion technique. The nanoparticles were further loaded with CpG fragments and used conjugated M2pep and α-pep
peptides on their surfaces to produce novel nano-complexes. The capability to target M2-like TAMs and anti-
tumor immunotherapy effects of nano-complexes were evaluated by flow cytometry and confocal microscopy in vitro. We also investigated the survival and histopathology of murine
melanoma models administrated with different nanocomplexes. Improvements in the tumor microenvironment for immune attack of
melanoma-bearing mice were also assessed. Results: The nano-complexes were effectively ingested by M2-like TAMs in vitro and in vivo, and the acidic lysosomal environment triggered the disintegration of
polydopamine from the nanoparticle surface, which resulted in the release of the payloads. The released CpG played an important role in transforming the M2-like TAMs into the M1-like phenotype that further secreted inflammatory
cytokines. The reversal of TAM released
cytokines and gradually suppressed
tumor angiogenesis, permitting the remodeling of the tumor microenvironment. Moreover, the activated TAMs also presented
antigen to T cells, which further stimulated the antitumor immune response that inhibited
tumor metastasis. Activated T cells released
cytokines, which stimulated NK cell infiltration and directly resulted in killing
tumor cells. The
baicalin released by M1-like TAMs also killed
tumor cells. Conclusion: The nano-complexes facilitated
baicalin,
antigen, and
immunostimulant delivery to M2-like TAMs, which polarized and reversed the M2-like TAM phenotype and remodeled the tumor microenvironment to allow killing of
tumor cells.