Imaging-guided
photodynamic therapy (PDT) holds great potential
for tumor therapy. However, achieving the synergistic enhancement
of the reactive oxygen species (ROS) generation efficiency and fluorescence
emission of photosensitizers (PSs) remains a challenge, resulting
in suboptimal image guidance and theranostic efficacy. The hypoxic
tumor microenvironment also hinders the efficacy of PDT. Herein, we
propose a “two-stage rocket-propelled” photosensitive
system for tumor cell ablation. This system utilizes MitoS, a mitochondria-targeted
PS, to ablate tumor cells. Importantly, MitoS can react with HClO
to generate a more efficient PS, MitoSO, with a significantly improved
fluorescence quantum yield. Both MitoS and MitoSO exhibit less O2-dependent type I ROS generation capability, inducing apoptosis
and ferroptosis. In vivo PDT results confirm that this mitochondrial-specific
type I–II cascade phototherapeutic strategy is a potent intervention
for tumor downstaging. This study not only sheds light on the correlation
between the PS structure and the ROS generation pathway but also proposes
a novel and effective strategy for tumor downstaging intervention.