A nano-innate immune system activator for cancer therapy in a 4T1 tumor-bearing mouse model.

BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy.

Recent progress in the understanding of complement activation and its role in tumor growth and anti-tumor therapy.

The complement system is indispensable in immune response, responsible for the wide range of immune surveillance, clearance and defense. Its activation, regulated by several crucial factors, is an important prerequisite for its role in tumor growth and anti-tumor therapy. Membrane attack complex (MAC) and anti-tumor anaphylatoxins like C5a have significant effects on promoting tumor, such as upregulation of oncogenic growth factors, activation of mitogenic signaling pathways and breakage of normal cell cycle. Complement cascades, initiated by anti-tumor antibodies, also play a pivotal role in anti-tumor therapy to suppress the tumor growth. Our review focuses on the recent progress in the understanding of complement activation and the role of it in tumor growth and anti-tumor therapy, in the context of rapid development of monoclonal antibodies and nanomaterials for cancer treatment.