Chlorin e6 (Ce6) is a widely utilized photosensitizer in photodynamic therapy (PDT) against tumor growth, but its hydrophobic feature and the hypoxia in the tumor microenvironment greatly compromise its therapeutic efficacy. To address the issues, here we designed a new Ce6 derivative (TCe6) by coupling Ce6 with amphiphilic D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), endowing Ce6 with an excellent amphiphilic feature. In particular, the overall reactive oxygen species (ROS) generation by TCe6 was significantly enhanced because TPGS could interact with mitochondrial complex II to induce extra ROS production, amplifying the total ROS production under PDT. Inspired by the unique property of α-cyano-4-hydroxycinnamate (CHC) in regulating lactate metabolism to spare more intracellular oxygen for PDT, TCe6 was further co-assembled with CHC to construct TCe6/CHC nanoparticles (NPs) for addressing the insufficient oxygen issue in PDT. The as-prepared TCe6/CHC NPs not only increased the efficiency of cell internalization but also improved the solubility and stability of Ce6 and CHC. Thanks to the extra ROS production by the TPGS unit, the amphiphilic feature of TCe6 and the CHC-mediated hypoxia microenvironment, the TCe6/CHC NPs demonstrated excellent PDT against tumor growth. This work provided a versatile strategy to solve the current bottleneck in photosensitizer-based PDT, holding great promise for the design of advanced photodynamic nanoplatforms.