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