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Xiangjie Gao, Guanxiong Lei, Bin Wang, Zhong Deng, Johannes Karges, Haihua Xiao, Donghui Tan

• Tumor immunotherapy has emerged as one of the most promising therapeutic methods to treat cancer. Despite its clinical application, the immunosuppressive tumor microenvironment compromises the therapeutic efficiency of this technique. To overcome this limitation, many research efforts have been devoted to the development of agents that reprogram the immunosuppressive tumor microenvironment through novel mechanisms. Over the last decade, compounds that intervene through the immunogenic stimulator of interferon genes (STING) pathway have emerged with potential for clinical development. Herein, the encapsulation of chemotherapeutic platinum complexes with a polymer with a cyclic seven-membered ring (PC7A)-based polymer into pH-responsive nanoparticles for multimodal therapeutically enhanced chemotherapy and immunotherapy is presented. This study represents the first nanomaterial with a dual activation mechanism of the STING pathway through DNA fragmentation as well as PC7A binding. The combination of these nanoparticles with immune checkpoint inhibitors demonstrates to nearly fully eradicate a colorectal tumor inside the mouse model by chemotherapy and immunotherapy using the STING pathway.