A hypoxic and acidic tumor microenvironment (TME) plays a significant role in cancer development through complex cellular signaling networks, and it is thus challenging to completely eradicate tumors via monotherapy. Here, PEGylated CoFe2O4 nanoflowers (CFP) with multiple enzymatic activities, serving as bioreactors responsive to TME cues, were synthesized via a typical solvothermal method for augmented sonodynamic therapy (SDT) and chemodynamic therapy (CDT) with elicitation of robust immune response. The CFP occupying multivalent elements (Co2+/3+, Fe2+/3+) exhibited strong Fenton-like and catalase-like activity. In another aspect, CFP itself is a brand-new sonosensitizer for high-performance SDT based on ultrasound-triggered electron (e-)/hole (h+) pair separation from the energy band with promptness and high efficiency. With efficient enrichment in tumorous tissue as revealed by magnetic resonance imaging, CPF could generate •OH for CDT relying on Fenton-like reactions. Moreover, catalase-mimicking CFP could react with endogenous H2O2 to generate molecular oxygen, and high O2 level may promote the production of 1O2 for SDT. What's more, the reactive oxygen species obtained from combined SDT/CDT could efficiently trigger immunogenic cell death through a synergistic therapy based on the elicitation of antitumor immunity with the aid of an immune checkpoint blockade for the sake of suppressing primary and distant tumors as well as lung metastasis. Taken together, this paradigm delivers useful insights for developing in-coming nanocomposites based on cobalt ferrite for cancer theranostics.