Photodynamic therapy (PDT) using oxygen-dependent type II photosensitizers is frequently limited by the hypoxic microenvironment of solid tumors. Type I photosensitizers show oxygen-independent reactive oxygen species (ROS) generation upon light irradiation but still face the challenges of aggregation-caused quenching (ACQ) and low efficiency to produce ROS. Herein, we first prepare an efficient type I photosensitizer from a perylene derivative via intramolecular donor-acceptor binding and sulfur substitution, which significantly enhance intersystem crossing between singlet and triplet states and electron transfer capability. After reaction with a type II photosensitizer, the covalent organic framework (COF) nanophotosensitizer is formed with alternated type I and II photosensitizer motifs in the same layer and staggered AB stacking between layers to avoid ACQ. The nanophotosensitizer exhibits high-efficiency generation of singlet oxygen (O) and superoxide anion radicals (O) via type I and II mechanism under normoxia upon exposure to light irradiation. Under hypoxia, massive O can be produced continuously. The potent ROS generation capability results in efficient cellular apoptosis and immunogenic cell death (ICD) efficiently. After combination with immune checkpoint inhibitors, tumor immunosuppressive microenvironment is reversed, which effectively ablates bulky hypoxic primary tumors and suppresses metastases via photodynamic immunotherapy. The COF nanophotosensitizers with staggered type I and II photosensitizer motifs represent a promising strategy to boost photodynamic immunotherapy of hypoxic tumors.