Figure 1. Tissue factor-activated coagulation cascade. The tissue factor (TF)-induced coagulation cascade is constantly activated in the tumor microenvironment because TF is overexpressed on tumor cell surfaces and inactive coagulation factors, including factors V (FV) and X (FX) (light blue circles), move out of the excessively permeable tumor vasculature.

The coagulation cascade is activated when TF forms a complex with factor VII (FVII), which is activated to FVIIa. The complex then induces a series of reactions that activate coagulation factor enzymes (dark blue circles), ultimately converting prothrombin to thrombin and fibrinogen to fibrin, activating blood clotting.

Liu et al. designed doxorubicin prodrugs that exploit the tumor-specific TF activation. The prodrugs are separately hydrolyzed by the TF:FVIIa complex and by thrombin in the tumor microenvironment, but not in the microenvironment of healthy tissue. This results in accumulation of doxorubicin in the tumor.