Photodynamic therapy (PDT) is a promising anticancer method due to its noninvasive features, high efficiency, and superior accuracy. The activated near-infrared upconversion photosensitizer has a high tissue penetration depth and could be explicitly released with minimal side effects. Therefore, we designed and synthesized a series of Br-substituted compounds (NFh-Br) based on the near-infrared upconversion hemicyanine dye. The heavy atomic effect improves the generation of 1 O 2 and upconversion luminous efficiency. Especially, NFh-Br 11 exhibited an excellent 1 O 2 generation rate under 808 nm excitation and effectively killed tumor cells in vitro, and the alkaline phosphatase (ALP)-activatable photosensitizer (NFh-ALP) was obtained by modifying the NFh-Br 11 . NFh-ALP could be activated by ALP and release NFh-Br 11 , which induces apoptosis of tumor cells and has outstanding anticancer effects in vitro and in vivo. This work could provide a strategy for designing activatable upconversion photosensitizers.