Highly efficient triplet photosensitizers (PSs) have attracted increasing attention in cancer photodynamic therapy where photo-induced reactive oxygen species (ROSs, such as singlet oxygen) are produced singlet-triplet intersystem crossing (ISC) of the excited photosensitizer to kill cancer cells. However, most PSs exhibit the fatal defect of a generally less-than-1% efficiency of ISC and low yield of ROSs, and this defect strongly impedes their clinical application. In the current work, a new strategy to enhance the ISC and high phototherapy efficiency has been developed, based on the molecular design of a thio-pentamethine cyanine dye (TCy5) as a photosensitizer. The introduction of an electron-withdrawing group at the -position of TCy5 could dramatically reduce the singlet-triplet energy gap (Δ ) value (from 0.63 eV to as low as 0.14 eV), speed up the ISC process ( = 1.7 ps), prolong the lifetime of the triplet state ( = 319 μs) and improve singlet oxygen (O) quantum yield to as high as 99%, a value much higher than those of most reported triplet PSs. Further and experiments have shown that TCy5-CHO, with its efficient O generation and good biocompatibility, causes an intense tumor ablation in mice. This provides a new strategy for designing ideal PSs for cancer photo-therapy.