Photodynamic therapy (PDT), which utilizes type I photoreactions, has great potential as an effective cancer treatment because of its hypoxia-tolerant superiority over the commonly used type II pathway. A few type I photosensitizers are exploited; however, they majorly induce cytotoxicity and possess poor tumor specificity and low-efficient theranostics. To resolve this issue, herein an aminopeptidase N (APN)-activated type I phototheranostic probe (CyA) is reported for anti-hypoxic PDT in conjunction with immunotherapy for effective cancer treatment. CyA can specifically activate near-infrared fluorescence, photoacoustic signals, and phototoxicity following APN-induced substrate cleavage and the subsequent generation of active phototheranostic molecules (such as CyBr). CyA endows specific imaging capabilities and effective phototoxicity toward tumor cells overexpressing APN under both normoxia and hypoxia. In addition, the locally activatable PDT induces systemic antitumor immune responses. More importantly, the integration of localized activated PDT and systemic immunotherapy evokes enhanced therapeutic effects with improved tumor inhibition efficiency in live mice compared with individual treatments. This study aims to present an activatable phototheranostic probe for effective hypoxia-tolerant PDT and combination therapy.