Neutrophils as emerging immunotherapeutic targets: Indirect treatment of tumors by regulating the tumor immune environment based on a sialic acid derivative-modified nanocomplex platform.

Tumor cells are dependent on their microenvironment; thus, targeting the non-cancerous components surrounding the tumor may be beneficial. Neutrophils are important inflammatory cells in the tumor microenvironment that significantly affect tumor cell proliferation, metastasis, and immune regulation. Targeted regulation of tumor-associated neutrophil-related pathways is expected to become a new therapeutic approach. Colchicine compounds are powerful anti-inflammatory drugs that strongly inhibit the chemotaxis of neutrophils to the inflammatory site. We attempted to achieve anticancer effects by utilizing its ability to inhibit neutrophil recruitment rather than killing tumor cells. As such drugs are likely to cause non-specific damages due to the lack of selectivity, we synthesized and used sialic acid and cholesterol derivatives (SA-CH) for surface modification of the newly synthesized low-toxic colchicine derivative (BCS) nanocomposite to improve neutrophil targeting. In vivo and in vitro experiments have shown that SA-CH-modified BCS preparations are effectively absorbed by neutrophils, inhibit cell migration, reduce infiltration of tumor-associated neutrophils, enhance T lymphocyte function, and exhibit good anti-S180 early tumor effect. In addition, in a triple-negative breast cancer model, the agent could strongly inhibit tumor metastasis to the lungs.