Tuning the oxidative stress-defense system plays a vital role in the treatment of breast tumors. In this study, a pyropheophorbide-a (PPa)-based prodrug nanoassembly is constructed by linking PPa with furoxan, a cysteine-depleting nitric oxide (NO) donor, through a disulfide bond. The as-prepared prodrug (NOSP) can assemble with distearoyl phosphoethanolamine-PEG2000 (DSPE-PEG2000) to form nanoassemblies in aqueous media. Following internalization by tumor cells, NOSP can respond to cysteine (Cys) and induce NO release to activate endogenous matrix metalloproteinases (MMP-1, -2), leading to collagen degradation and improved drug delivery. In addition, Cys consumption can impede the biosynthesis of glutathione (GSH), while NOSP can react with high levels of intracellular GSH within seconds, thus synergizing photodynamic therapy against breast tumors and distant metastasis.