Apoptotic cell mimics enhance immunogenic cell death and inflame tumor microenvironment by modulating macrophages

Macrophages play a crucial role in regulating the efficacy of immunotherapy. However, the tumor microenvironment (TME) educated macrophages into immune-suppressive phenotypes. The suppressive effects are largely caused through the clearance of apoptotic cells and secretion of anti-inflammatory cytokines. Here, we propose that apoptotic cell-mimicking liposomes (PS_x) that contain phosphatidylserine reduce the phagocytosis of apoptotic tumor cells by interacting with various phosphatidylserine-recognizing phagocytotic receptors on macrophages. Uncleared apoptotic tumor cells undergo secondary necrosis, leading to the abundant release of tumor antigens and immunostimulants, thus causing immunogenic cell death (ICD). TLR7/8 agonists are further loaded as model agonists in liposomes (R@PS_x) to reverse the suppressive tumor microenvironment. These apoptotic cell mimics successfully induce a cytotoxic T-cell response and lead to tumor regression in different tumor models. This work provides a novel strategy to enhance the therapeutic effect of ICD and inflame the TME by modulating the function of macrophages.