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The alternations in the hypoxic and immune microenvironment are closely related to the therapeutic effect and prognosis of oral squamous cell carcinoma (OSCC). Herein, a new nanocomposite, TiOsub2/sub@Ru@siRNA is constructed from a ruthenium-based photosensitizer (Ru) modified-TiOsub2/subnanoparticles (NPs) loaded with siRNA of hypoxia-inducible factor-1α (HIF-1α). Under visible light irradiation, TiOsub2/sub@Ru@siRNA can elicit both Type I and Type II photodynamic effects, which causes lysosomal damage, HIF-1α gene silencing, and OSCC cell elimination efficiently. As a consequence of hypoxia relief and pyroptosis induction, TiOsub2/sub@Ru@siRNA reshapes the immune microenvironment by downregulation of key immunosuppressive factors, upregulation of immune cytokines, and activation of CD4sup+/supand CD8sup+/supT lymphocytes. Furthermore, patient-derived xenograft (PDX) and rat oral experimental carcinogenesis models prove that TiOsub2/sub@Ru@siRNA-mediated photodynamic therapy significantly inhibits the tumor growth and progression, and markedly enhances cancer immunity. In all, this study presents an effective hypoxia-adaptive photo-immunotherapeutic nanosystem with great potential for OSCC prevention and treatment.