IL12-based phototherapeutic nanoparticles through remodeling tumor-associated macrophages combined with immunogenic tumor cell death for synergistic cancer immunotherapy

Various cancer therapeutic strategies have been designed for targeting tumor-associated macrophages (TAMs), but TAM reprogramming-based monotherapy is often clinically hindered, likely due to the lack of a coordinated platform to initiate T cell-mediated immunity. Herein, we fabricated reactive oxygen species (ROS)-responsive human serum albumin (HSA)-based nanoparticles (PEG/IL12-IA NPs) consisting of indocyanine green (ICG), arginine (Arg), and interleukin 12 (IL12). Upon laser irradiation, the nanoparticles were found to be able to dissociate, thus facilitating the release of IL12. On the one hand, the phototherapy effects produced by ICG could induce immunogenic cell death (ICD) of tumor cells, activate dendritic cells (DCs) and initiate T cell-mediated immunity. On the other hand, the ROS responsively released IL12 from the PEG/IL12-IA NPs could reprogramme the immunosuppressive M2-TAMs to M1-TAMs, which could further convert Arg to nitric oxygen (NO), thus alleviating immunosuppression and enhancing antitumor immunity. Based on this combined therapeutic effect, the nanoparticles inhibited the tumor growth, prolonged the survival time, delayed lung metastasis, and ultimately improved the antitumor immuno-therapeutic efficiency in 4T1-bearing mice. Taken together, remodeling TAMs combined with phototherapy-induced ICD <i>via</i> the PEG/IL12-IA NPs is a promising cancer immunotherapy strategy for boosting both innate and adaptive antitumor immunity.