Polarization of tumor-associated macrophages by TLR7/8 conjugated radiosensitive peptide hydrogel for overcoming tumor radioresistance

Radioresistance reduces the antitumor efficiency of radiotherapy and further restricts its clinical application, which is mainly caused by the aggravation of immunosuppressive tumor microenvironment (ITM). Especially tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype during high-dose fractional radiotherapy mediating radiotherapy resistance. Herein, the toll like receptor agonist TLR7/8a was conjugated with radiosensitive peptide hydrogel (Smac-TLR7/8 hydrogel) to regulate TAMs repolarization from M2 type into M1 type, thus modulating the ITM and overcoming the radioresistance. The Smac-TLR7/8 hydrogel was fabricated through self-assembly with nanofibrous morphology, porous structure and excellent biocompatibility. Upon gamma-ray radiation, Smac-TLR7/8 hydrogel effectively polarized the macrophages into M1 type. Notably, combined with radiotherapy, TAMs repolarization regulated by Smac-TLR7/8 hydrogel could increase tumor necrosis factor secretion, activate antitumor immune response and effectively inhibit tumor growth. Moreover, TAMs repolarization rebuilt the ITM and elicited the immunogenic phenotypes in solid tumors, thus enhanced the PD1-blockade efficacy through increasing tumor infiltrating lymphocytes (TILs) and decreasing Treg cells in two different immune activity tumor mice models. Overall, this study substantiated that recruiting and repolarization of TAMs were critical in eliciting antitumor immune response and overcoming radioresistance, thus improving the efficacy of radiotherapy and immunotherapy.