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Tumor hypoxia is a fundamental hallmark of the solid tumor microenvironment (TME) that severely impairs the efficacy of oxygen-dependent treatments, such as photodynamic therapy (PDT), and drives therapeutic resistance. Overcoming this biological barrier is critical for improving clinical outcomes. This review comprehensively summarizes recent advancements in oxygen-modulating nanobiomaterials designed to tame the hypoxic TME and sensitize tumors to multimodal therapies. We systematically evaluate two primary nanomedicine strategies: exogenous oxygen delivery systems (including hemoglobin-based carriers, perfluorocarbons, and metal-organic frameworks) and in situ oxygen-generating catalysts (such as catalase, solid peroxides, and photocatalytic nanomaterials). Furthermore, nanotechnology-driven approaches for vascular normalization and enhancing oxygen diffusion are discussed. By focusing on material design, we elucidate how stimuli-responsive and actively targeted nanocarriers achieve precise, on-demand TME regulation. Crucially, we explore how these oxygen-enhancing platforms synergize with conventional treatments to reverse therapeutic resistance, enabling robust integrated regimens that combine PDT with chemotherapy, photothermal therapy (PTT), and gas therapy. Finally, we outline current translational challenges, such as nanoparticle stability, deep tumor penetration, and biosafety-and provide perspectives on developing intelligent, multifunctional nanomedicines to definitively break the barrier of tumor hypoxia. To provide a forward-looking paradigm, this review uniquely highlights the disruptive integration of artificial intelligence (AI) in nanomedicine design, single-atom catalysts (SACs) for oxygen-independent Type I PDT, and covalent photosensitizers.