Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are both promising cancer treatments to inhibit tumor cells by generating highly cytotoxic reactive oxygen species (ROS). Herein, we report a novel tumor microenvironment (TME) stimulus-responsive water-soluble glycosylated photosensitizer (BT-TPE@Fe-Lac), which can serve as a high-efficiency antitumor agent by combining PDT and CDT, based on the coordination of Fe with lactosyl bis(2-pyridylmethyl)amine and an AIE luminogen (benzothiazole-hydroxytetraphenylethene, BT-TPE). BT-TPE@Fe-Lac is stable under physiological conditions and selectively targets HepG2 cells asialoglycoprotein receptor (ASGPR)-mediated endocytosis. It rapidly dissociates into AIE-active BT-TPE molecules and a lactosyl ferric(III) complex in the acidic lysosomes of cancer cells. Upon exposure to light, BT-TPE produces O˙ radicals for type I PDT. The ferric(III) complex is reduced to an Fe(II) complex upon depletion of glutathione, which primes the breakdown of endogenous HO within the tumor microenvironment, thus generating highly toxic ˙OH for enhanced CDT. Compared with the monotherapy of PDT or CDT, BT-TPE@Fe-Lac can significantly increase the intracellular ROS levels to induce more tumor cell death under low drug doses and hypoxia-dependent conditions. This strategy leverages the unique properties of the TME to optimize therapeutic outcomes, offering a promising approach for the TME-responsive nanoplatform in advanced cancer therapy.