FePt-Cys nanoparticles (FePt-Cys NPs) have been well used in many fields, despite their poor solubility and stability. We synthetized a cysteine surface modified FePt NPs, which exhibited good solubility, stability and biocompatibility. We explored the insight mechanisms of the antitumor effects of this new nanoparticle system in lung cancer cells. In the in vitro study, FePt-Cys NPs induced a reactive oxygen species (ROS) burst, which suppressed the antioxidant protein expression and induced cell apoptosis. Furthermore, FePt-Cys NPs prevented the migration and invasion of H1975 and A549 cells. These changes were correlated with a dramatic decrease in MMP-2/9 expression and enhanced the cellular attachment. We demonstrated that FePt-Cys NPs promoted the effects of chemo-radiation through activation of the caspase system and impairment of DNA damage repair. In the in vivo study, no severe allergies or drug-related deaths were observed and FePt-Cys NPs showed a synergistic effect with cisplatin and radiation. In conclusion, with good safety and efficacy, FePt-Cys NPs could therefore be potential sensitizers for chemoradiotherapy.