Direct hypoxia alleviation and lactate depletion in the tumor microenvironment (TME) are promising for effective cancer therapy but still very challenging. To address this challenge, the current research directly reshapes the TME for inhibiting tumor growth and activating the antitumor immunity using a drug-free nanozyme. Herein, the acid-sensitive nanozymes were constructed based on peroxidized layered double hydroxide nanoparticles for O self-supply and self-boosted lactate depletion. The coloading of partially cross-linked catalase and lactate oxidase enabled the acid-sensitive nanozymes to promote three reactions, that is, (1) HO generation from MgO hydrolysis (30% at pH 7.4 vs 63% at pH 6.0 in 8 h); (2) O generation from HO (12% at pH 7.4 vs 21% at pH 6.0 in 2 h); and (3) lactate depletion by in situ generated O (50% under hypoxia vs 75% under normoxia in 24 h in vitro) in parallel or tandem. These promoted reactions together efficiently induced colon cancer cell apoptosis under the hypoxic conditions, significantly inhibited tumor growth (>95%), and suppressed distant tumor growth upon seven administrations in every 3 days and moreover transformed the immunosuppressive tumor into "hot" one in the colon tumor-bearing mouse model. This is the first example for a nanozyme that supplies sufficient O for hypoxia relief and lactate depletion, thus providing a new insight into drug-free nanomaterial-mediated TME-targeted cancer therapy.