Death pathway plasticity in therapy resistance: mechanistic switches and translational opportunities

Abstract Regulated cell death (RCD) programs in cancer have traditionally been framed as discrete pathways defined by signature effectors, including caspases (apoptosis), RIPK1–RIPK3–MLKL (necroptosis), gasdermins (pyroptosis), lipid peroxidation control nodes (ferroptosis), PARP1–AIF/MIF (parthanatos), and FDX1-dependent lipoylation stress (cuproptosis). Here, we advance an integrated view in which these programs function as a configurable decision network rather than isolated routes. Therapeutic and microenvironmental inputs, such as death ligands, chemoradiotherapy, targeted agents, PARP inhibition, copper ionophores, nutrient/oxidative stress, extracellular matrix detachment, and cytotoxic T-cell pressure, converge on shared hub modules that act as rheostats, routing cells toward distinct execution outcomes or into drug-tolerant persister states. This circuit-level framing explains context-dependent switching and mixed phenotypes, including caspase-8/c-FLIP control of apoptosis–necroptosis, caspase–gasdermin coupling of apoptosis–pyroptosis, and metabolic–redox tuning of ferroptosis susceptibility via SLC7A11–GPX4–ACSL4–FSP1 and autophagy-linked lipid/iron handling. We outline a biomarker and functional assay framework to map tumor death wiring from biopsies and organoid challenges, enabling rational combination strategies that exploit death program plasticity while anticipating resistance and inflammatory toxicities.