Engineered Oxygen Factories Synergize with STING Agonist to Remodel Tumor Microenvironment for Cancer Immunotherapy

Abstract Immunotherapy is a revolutionary achievement in cancer treatment. However, inadequate immune cells infiltration in tumor microenvironment (TME) always leads to treatment failure. Moreover, hypoxic TME hampers normal functions of immune cells. Here, it is found that hypoxia suppresses the STING signaling and immune cells activation in the work. Remodeling tumor immune microenvironment and relieving hypoxia are thus essential for enhancing immunotherapy efficiency. Herein, a spirulina platensis (SP)‐based magnetic biohybrid system is constructed as an oxygen factory and loaded with stimulator of interferon genes (STING) agonist ADU‐S100 (ADU@Fe‐SP) for tumor immunotherapy. Magnet‐guided biohybrid SP can actively target tumor tissues and produce oxygen in situ through photosynthesis, which reverses the hypoxic TME and facilitates the function of immune cells. Besides, the targeted delivery of ADU‐S100 can activate the STING/TBK1/IRF3 signaling and boost cytokines production in tumor and innate immune cells. The ADU@Fe‐SP system thus induces efficient immune cells infiltration in TME, which efficiently inhibits tumor progression and significantly enhances anti‐PD‐1 therapy efficiency in SCC VII‐bearing tumor xenograft. ADU@Fe‐SP exerts antitumor effect in a STING‐dependent manner by in vivo STING‐knockout mice model. The efficiency of this immunotherapy strategy is also demonstrated in patient‐derived xenograft model originating from oral cancer, showing great clinical potential.