Sponge-like nano-system suppresses tumor recurrence and metastasis by restraining myeloid-derived suppressor cells-mediated immunosuppression and formation of pre-metastatic niche

Abstract

Tumor recurrence and metastasis still greatly limit the therapeutic efficiency on the majority of postoperative clinical cases. With the aim to realize more powerful treatment outcomes on postoperative malignant tumors, a sponge-like neutrophil membrane-coated nano-system (NM/PPcDG/D) was fabricated to inhibit tumor recurrence and metastasis by inhibiting the recruitment and functions of myeloid-derived suppressor cell (MDSCs), which reinforced anti-tumor immunity and also suppressed pulmonary metastasis by inhibiting the formation of pre-metastatic niche (PMN). Firstly, PPcDG/D nanoparticles (NPs) were formulated by the self-assembling and crosslinking of synthesized redox-responsive polymer (PPDG) with doxorubicin (DOX) loading in the nanocore (PPcDG/D), followed by coating with activated neutrophils membrane to fabricate biomimetic NM/PPcDG/D. The sponge-like NM/PPcDG/D not only showed obvious natural tropism to postoperative inflammatory site, but also inhibited the recruitment and functions of MDSCs, thus relieved MDSCs-mediated immunosuppression. Additionally, NM/PPcDG/D also suppressed the formation of PMN to inhibit pulmonary metastasis by reducing the recruitment of MDSCs, decreasing the permeability of pulmonary vessels and inhibiting the implantation of circulating tumor cell (CTCs). Eventually, this fabricated NM/PPcDG/D NPs significantly inhibited tumor recurrence and metastasis on postoperative triple negative breast cancer (TNBC) model, presenting a promising therapeutic strategy on postoperative malignant tumors. STATEMENT OF SIGNIFICANCE: Myeloid-derived suppressor cells (MDSCs) play important roles in accelerating tumor recurrence and metastasis by promoting the establishment of immunosuppression in postoperative inflammatory regions and facilitating the formation of pulmonary pre-metastasis niche (PMN). In order to achieve enhanced suppression of recurrence and metastasis, a sponge-like NM/PPcDG/D nano-system was designed and fabricated. This nano-system is also the first attempt to integrate the regulation effects of a nano-sponge and anti-inflammatory agent to achieve enhanced multi-mode manipulation of MDSCs. Ultimately, NM/PPcDG/D powerfully restrained the recurrence and spontaneous metastasis on TNBC model. This article also revealed the particular roles of MDSCs involved in the regulation networks of postoperative recurrence and metastasis, immunosuppression and inflammation.

Keywords: Immunosuppression and inflammation; Membrane-coated nano-system; Myeloid-derived suppressor cells; Postoperative recurrence and metastasis; Pre-metastatic niche.