Exploiting vitamin C as a prooxidant to activate ROS-responsive prodrugs for potent and selective tumor killing

Developing targeted cancer therapy with minimal side effects remains a significant challenge. Oxidative stress-based cancer therapies have gained traction in recent years. However, challenges such as limited tumor selectivity and therapeutic durability often hinder their clinical application. Here, we report a novel strategy of combining ROS-responsive prodrugs with prooxidants to achieve potent, durable, and selective tumor killing effects. This approach leverages pro-oxidants (i.e. ascorbate) to amplify oxidative stress within tumors, sensitizing cancer cells to ROS-responsive prodrugs. Both in vitro and in vivo studies confirm the anticancer synergism and selectivity of this combination therapy, which achieved complete tumor regression without recurrence, significantly outperforming single-agent treatments. This combination therapy is effective against hard-to-treat cancers like triple-negative breast cancers. Our findings highlight the potential of targeting tumor redox mechanisms through a combination of ROS-responsive prodrugs and pro-oxidants, offering a promising avenue for repurposing these agents in cancer therapy.