Abstract: [Objective] Carbon capture and storage (CCS) is crucial in combating global climate change, and deep saline aquifers have the largest identified storage potential, making them the preferred storage location. However, when CO2 is injected underground, it tends to escape through interconnected fractures or reactivated faults toward the ground due to buoyancy. Thus, studying the impact of CO2 injection on fault and the feedback effect of fault activation on CO2 leakage is significant. [Methods] In this paper, we develop a fully coupled two-phase thermo-hydro-mechanical model to simulate mutual interactions between CO2 injection, fault failure, and CO2 plume propagation. [Results] Modeling results demonstrate that the permeability distribution exhibits a notable dichotomy upon fault activation. Furthermore, the evolution of fault permeability is intimately coupled with the spatio-temporal changes in the pore pressure field. As the initial failure zone transforms into a high-permeability area, it facilitates the release of pore pressure, dampening further fault activation, and leading to localized activation characteristics. In addition, the migration range of CO2 plumes cannot be trivially equated with the cooled zone in the rock mass. The plume dispersal is rapid and extensive, reaching a frontal migration distance of up to 1500 m after just two years of constant injection. In contrast, the diffusion of the temperature field is slow and concentrated, yielding a cooled area of only 200 m after 20 years of constant injection. This constrained temperature field pattern is less prone to inducing fault activation, thereby contributing to the long-term safety of carbon sequestration projects. Finally, fault configuration exerts a significant influence on the long-term safety of CO2 storage, with reverse faults exhibiting the best sealing performance, normal faults the worst, and strike-slip faults falling in between. Specifically, the effective CO2 storage capacity of the reverse fault is approximately 25% higher than that of the normal fault. [Conclusion] In conclusion, the established two-phase thermo hydro mechanical model incorporating damage behavior demonstrates robust performance, accurately capturing the intricate interaction mechanisms between fault progressive failure and CO2 plume migration. This model provides both theoretical and technical support for the long-term safety assessment of carbon sequestration projects.