Figure 9.

(A) Schematics show that simultaneous activation of the CSF1R pathway and the CD47-SIRPα pathway by cancer cells resulting in M2 polarized protumorigenic macrophages. (B) Schematics show deterministic co-delivery of DNTs to the M2 polarized macrophage leads to concurrent inhibition of CSF1R and SHP2, which results in repolarization of macrophages to an antitumorigenic M1 phenotype while simultaneously increasing the phagocytic index. Adapted with permission from ⁸², copyright 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Preparation of HPT-PF NPs loading with Cas9/sgRNA and pIL-12 plasmids. (D) Schematic illustration of MMP2/9 response and CPP-mediated tumor targeting of HPT-PF NPs, and IL-12 production and Cas9/sgRNA complexes-induced CD47 knockout by the transfection of Cas9/sgRNA and pIL-12 plasmids in melanoma cells. (E) Schematics show that the combination of CD47 blockade with IL-12 production synergistically promotes the M1-polarized TAMs for enhanced phagocytosis and secretion of inflammatory factors to elicit TAM-mediated immunotherapy. Adapted with permission from ⁵⁷, copyright 2021 Elsevier Ltd. Abbreviations: MCSF: macrophage colony stimulating factor; CSF1-R: colony stimulating factor 1 receptor; SIRPα: signal regulatory protein α; SHP: Src homology region 2 (SH2) domain-phosphatase; PF: fluorinated polyethylenimine; HPT: hyaluronic acid-polyethylene glycol-tumor microenvironment sensitive peptides; CPP: cell-penetrating peptides; MMP-2/9: matrix metalloproteinases-2/9.