Cellular plasticity as a dynamic regulator of death sensitivity and drug resistance in cancer

Therapeutic resistance continues to be a major obstacle to long-term cancer treatment, regardless of the improvement of chemotherapy, radiotherapy, and targeted therapies. There is an emerging body of evidence that resistance is caused not only by irreversible genetic changes but also by dynamic, reversible adaptations collectively referred to as cellular plasticity. Cellular plasticity facilitates the conversion of the cancer cell's phenotypic state to respond to therapeutic stress conditions and, consequently, changes the survival signals and sensitivity of regulated cell death. This review describes the mechanistic interplay between cellular plasticity and death sensitivity, in which adaptive transitions favoring tumor cells in response to treatment induce drug resistance and promote tumor cell survival. Examples of important plasticity programs include epithelial-mesenchymal plasticity (EMP), cancer stem cell (CSC) phenotypes, and drug-tolerant persister (DTP) states, which enable tumor cells to temporarily escape cytotoxic stress through coordinated transcriptional, metabolic, and epigenetic reprogramming. The adaptive states are linked to diminished apoptotic priming, stimulated cytoprotective autophagy, altered vulnerability to ferroptosis, and senescence-like survival. Even though it is reversible in the early stages, it can progress to permanent resistance through the accumulation of stable genetic and epigenetic changes that result from prolonged persistence. Attacking vulnerabilities associated with these adaptive states, e.g., epigenetic control, metabolic addictions, ferroptotic programs, and stem-like signaling, might be promising strategies to eliminate therapy-resistant tumor cells and enhance overall therapeutic responses.