The hypoxic tumor microenvironment (TME) of osteosarcoma (OS) is the Achilles’ heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the hypoxia. Herein, we proposed a “reducing expenditure of O2 and broadening sources” dual-strategy and constructed ultrasmall IrO2@BSA-ATO nanogenerators (NGs) for decreasing the O2-consumption and elevating the O2-supply simultaneously. As O2 NGs, the intrinsic catalase (CAT) activity could precisely decompose the overexpressed H2O2 to produce O2 in situ, enabling exogenous O2 infusion. Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O2 conservation. As a result, IrO2@BSA-ATO NGs systematically increase tumor oxygenation in dual ways and significantly enhance the antitumor efficacy of PDT. Moreover, the extraordinary photothermal conversion efficiency allows the implementation of precise photothermal therapy (PTT) under photoacoustic guidance. Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO2@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both in vitro and in vivo. Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO2@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.