Immunosuppressive triangle depletion through the combination punches strategy for enhanced immunotherapy

Tumor immunotherapy non-responders often have high levels of tumor-associated macrophages (TAMs), circulating myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), which form a vicious “immunosuppressive triangle” to promote tumor growth and metastasis. Rather than single immunosuppressive cell modulation in some reports, it is more meaningful to precisely target as well as overall deplete the immunosuppressive triangle for enhanced immunotherapy. To achieve this, a pH/matrix metalloproteinase-2 (MMP2) dual responsive nanoplatform was constructed. The acidic sensitive poly β-amino esters-polyethylene glycol nanoparticles (PAE-PEG NPs) loaded with liver-X-receptor agonist GW3965 were prepared, and then were decorated with MMP2 sensitive M2-TAMs targeted apoptotic peptides (PEP) to obtain GW3965@PAE-PEG-PEP (GW@PPP). After reaching tumor microenvironment, the combination punches strategy based on this nanoplatform was implemented. As one punch, the MMP2 cleaved PEP segments induced M2-TAMs apoptosis specifically. As another punch, the acidic responsive GW3965 release promoted immunoregulatory apolipoprotein E (ApoE) transcription, further inhibiting the survival of MDSCs, tumor cells and endothelial recruitment. In addition, Tregs, the formation and recruitment of which was related to MDSC and TAMs, were suppressed subsequently. Overall, the GW@PPP directly drove immunosuppressive triangle depletion and further immune response, which effectively prevented tumor growth and metastasis for enhanced immunotherapy in an all-round way.