TLR7/8 Agonist and SHP2 Inhibitor Loaded Nanoparticle Enhances Macrophage Immunotherapy Efficacy

Abstract Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the solid tumor microenvironment, making them an attractive target for cancer immunotherapy. However, there are two important challenges. First, tumors repolarize the TAMs predominantly to M2 tumor‐aiding phenotype by secreting various immunosuppressive cytokines. Second, CD47 on cancer cells interacts with signal‐regulating protein a (SIRPa) expressed on macrophages. This crosstalk provides a downregulatory signal in the form of activation of SHP1/2 that inhibits cancer cell phagocytosis. These challenges can be overcome by engineering a nanoparticle that can deliver a rationale combination of immunomodulatory agents to the TAMs that can repolarize the M2 macrophages to M1 phenotype efficiently and concurrently block CD47‐SIRPa interactions by inhibiting SHP2 signaling. A lipid nanoparticle (LNP) system loaded with amphiphilic R848‐cholesterol (TLR7/8 agonist) and SHP099 (SHP2 inhibitor) in a predefined ratio has been designed. In vitro studies show that the LNPs system repolarized to M2 macrophages to M1 phenotype and expressed co‐stimulatory molecules while enhancing phagocytic potential. In vivo efficacy studies in 4T1 tumor‐bearing mice show that LNPs exhibit superior anti‐tumor efficacy than other treatments. Thus, the lipid nanoparticle‐mediated co‐delivery of a rational combination of TLR7/8 agonist and SHP2 inhibitor in the TAMs can enhance macrophage immunotherapy.