AUTHOR=Bülbül Muhammet Volkan , Demircan Turan 
  
TITLE=Death plasticity in cancer: a network perspective on regulated cell death pathways and their therapeutic exploitation
  
JOURNAL=Pathology and Oncology Research
  
VOLUME=Volume 32 - 2026
  
YEAR=2026
  
URL=https://www.por-journal.com/journals/pathology-and-oncology-research/articles/10.3389/pore.2026.1612568
  
DOI=10.3389/pore.2026.1612568
  
ISSN=1532-2807
  
ABSTRACT=For most of the twentieth century, apoptosis was regarded as the principal—if not sole—regulated route to cellular self-destruction, and cancer therapy was designed accordingly. Over the past decade, however, the discovery of mechanistically distinct regulated cell death (RCD) modalities—ferroptosis, pyroptosis, necroptosis, cuproptosis, disulfidptosis, PANoptosis, and a broader non-canonical landscape encompassing autophagy-dependent death, anoikis, entosis, parthanatos, and lysosomal cell death—has reframed resistance to cell death as a composite phenotype rather than a single evaded pathway. This review synthesizes the molecular executors, cancer-specific evasion mechanisms, and immunological consequences of each RCD modality, before shifting to the network level to examine the master regulatory axes (phosphoinositide 3-kinase (PI3K)–AKT–mechanistic target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1), p53, and Wnt/β-catenin) and metabolic reprogramming events (the Warburg shift) through which single oncogenic alterations confer broad-spectrum death resistance. Particular attention is given to the immunogenicity of different death modalities within the tumor microenvironment, where lytic pathways that release damage-associated molecular patterns (DAMPs), such as necroptosis, pyroptosis, and cuproptosis, can convert immunologically cold tumors into those responsive to checkpoint blockade, in contrast to the immunologically silent execution of apoptosis. The review concludes by identifying the principal barriers to clinical translation—context-dependent death sensitivity, a scarcity of validated pharmacological probes for non-apoptotic pathways, contradictory immunological findings, tumor metabolic heterogeneity, and the absence of standardized clinical biomarkers—and outlines emerging directions, including proteolysis-targeting chimera (PROTAC)-based degradation of resistance nodes, composite multi-pathway death signatures, and single-cell/spatial approaches capable of resolving death competence at cellular resolution. Understood as a plastic, network-level capability rather than a switch to be thrown, cancer cell death offers a substantially larger and more combinable therapeutic target space than the apoptosis-centric paradigm alone.