Chemodynamic therapy (CDT) is an innovative and effective treatment that relies on the Fenton or Fenton-like reaction, in which endogenous H2O2 overproduction is converted into cytotoxic hydroxyl radicals (•OH) to suppress tumor growth. Nevertheless, the therapeutic efficiency of CDT is severely restricted by undesirable properties, such as reaction conditions and catalyst performance. Herein, a 2D Ti3C2 MXene/Cu2O nanosheet (MCP NS)-based multifunctional nanoplatform (3-BP@MCG NSs) has been constructed, in which glucose oxidase (GOx) and respiration inhibitor 3-bromopyruvate (3-BP) are sequentially embedded. In this structure, the copper-based catalyst Cu2O releases Cu+ in an acid-triggered manner in the tumor microenvironment (TME), which activates the Fenton-like reaction to catalyze the generation of •OH for CDT. The composite has excellent photothermal properties and a high-resolution photoacoustic imaging (PAI) capability in the near-infrared (NIR) region, and especially under NIR irradiation, the photothermal effect generated by the nanosheets accelerates catalysis. GOx is a natural enzyme catalyst for depleting glucose and oxygen content in cells, upregulating H2O2 levels in situ, and thereby improving the therapeutic effect of CDT. What is more, the supported 3-BP not only reduces oxygen consumption to alleviate hypoxia levels but also inhibits the glycolysis process and lowers ATP levels by suppressing hexokinase activity. As a result, 3-BP@MCG NSs optimize the unique properties of MCP NSs, GOx, and 3-BP via mutual promotion, realizing self-enhanced PTT/CDT synergistic therapy. This work establishes an emerging strategy for highly efficient PAI-guided integrated treatment and provides a proof of concept for the cooperation of hypoxia relief and in situ H2O2 and NIR synergistic enhancement to improve therapeutic efficiency.