Dual Enzyme-Driven\nCascade Reactions Modulate Immunosuppressive\nTumor Microenvironment for Catalytic Therapy and Immune Activation

Lactate-enriched tumor microenvironment (TME) fosters\nan immunosuppressive\nmilieu to hamper the functionality of tumor-associated macrophages\n(TAMs). However, tackling the immunosuppressive effects wrought by\nlactate accumulation is still a big challenge. Herein, we construct\na dual enzyme-driven cascade reaction platform (ILH) with immunosuppressive\nTME modulation for photoacoustic (PA) imaging-guided catalytic therapy\nand immune activation. The ILH is composed of iridium (Ir) metallene\nnanozyme, lactate oxidase (LOx), and hyaluronic acid (HA). The combination\nof Ir nanozyme and LOx can not only efficiently consume lactate to\nreverse the immunosuppressive TME into an immunoreactive one by promoting\nthe polarization of TAMs from the M2 to M1 phenotype, thus enhancing\nantitumor defense, but also alleviate tumor hypoxia as well as induce\nstrong oxidative stress, thus triggering immunogenic cell death (ICD)\nand activating antitumor immunity. Furthermore, the photothermal performance\nof Ir nanozyme can strengthen the cascade catalytic ability and endow\nILH with a PA response. Based on the changes in PA signals from endogenous\nmolecules, three-dimensional multispectral PA imaging was utilized\nto track the process of cascade catalytic therapy in vivo. This work\nprovides a nanoplatform for dual enzyme-driven cascade catalytic therapy\nand immune activation by regulating the immunosuppressive TME.