Reframing cancer therapy through tumor plasticity

A major barrier to cancer therapy is the emergence of drug-tolerant states that allow tumor cells to bypass the targeted pathway. These refractory states arise through reversible cellular plasticity, a process that also occurs during development and regeneration, giving rise to new lineages or phenotypes and restoring drug sensitivity upon treatment withdrawal. Over time, genetic mutations may accumulate, leading to permanent resistance. This paradigm expands the focus from targeting genetic mechanisms alone to also exploiting nongenetic vulnerabilities, driving clinical strategies that prevent or eliminate plastic and transformed populations. Here, we provide an overview of nongenetic plasticity mechanisms and their emerging clinical applications.