Chimeric Peptide Engineered Bioregulator for Metastatic Tumor Immunotherapy through Macrophage Polarization and Phagocytosis Restoration

Abstract

Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.

Engineering nanoparticles-enabled tumor-associated macrophages repolarization and phagocytosis restoration for enhanced cancer immunotherapy

“…SHP099, as a SHP2 allosteric inhibitor, has shown promising results in facilitating the engulfment of tumor cells by macrophages in the previous works [ 23 , 24 ]. To determine whether SHP099-loaded HSA nanoparticles could promote the phagocytosis by macrophages, CT26 cells were marked with cell tracker green (CTG, green) and then co-cultured with RAW264.7 in vitro, which had been pre-treated with the different SHP099 formulations (Fig.…”

“…Tumor cells may express high levels of CD47 on their surface, which can bind with signal regulatory protein alpha (SIRPa) receptor on macrophages, resulting in a "don't eat me" signal and phagocytosis inhibition [19,20]. CD47-SIRPa axis-blocking agents such as Hu5F9-G4, ALX148, and SHP099 (a SHP-2 inhibitor) have been widely applied for cancer treatment [21][22][23][24]. Although promising, given that the broad expression of CD47 in healthy cells, systemic infusion of CD47 inhibitors can cause the limited efficacy and adverse effects such as anemia [25,26].…”

Recent Advances in Nanoimmunotherapy by Modulating Tumor-Associated Macrophages for Cancer Therapy

“…SHP099 worked as a SHP-2 inhibitor that downregulated SHP-2 expression and can further inhibit the expression of SIRPα. After being internalized, R848 and SHP099-loaded ChiP-RS polarized M2 macrophages to the M1 phenotype and enhanced the phagocytosis of tumor cells by M1 macrophages, resulting in effective inhibition of metastatic tumors . Zhao et al fused CD47 nanobodies (CD47nb) onto the surface of outer membrane vesicles (OMVs) derived from bacteria.…”