A comprehensive review published in Pathology and Oncology Research synthesizes the molecular mechanisms underlying cancer’s resistance to regulated cell death. The study argues that tumor cells do not merely evade apoptosis, the historically dominant form of programmed cell death, but instead develop a composite phenotype that suppresses a broad network of distinct death modalities. By reframing resistance as a plastic, network-level capability rather than a single evaded pathway, the review highlights a substantially larger therapeutic target space for oncology.
The authors, MVMuhammet Volkan Bülbül and Turan Demircan, examine the landscape of regulated cell death (RCD) that has expanded significantly over the past decade. Beyond apoptosis, the catalogue now includes ferroptosis, pyroptosis, necroptosis, cuproptosis, disulfidptosis, and PANoptosis. Each modality is mechanistically distinct, controlled by dedicated executors, and differentially altered in cancer. This expanded taxonomy changes cancer biology by revealing that resistance is a composite phenotype assembled through the simultaneous suppression of more than a dozen death programs.
Central to this network architecture are master regulatory axes that confer broad-spectrum death resistance through single oncogenic alterations. The review identifies the PI3K-AKT-mTOR pathway, the NRF2-KEAP1 antioxidant transcriptional program, the p53 tumor suppressor network, and Wnt/β-catenin signaling as key hubs. For instance, constitutive activation of PI3K-AKT-mTOR suppresses apoptosis by inactivating BAD and stabilizing MDM2, while simultaneously protecting against ferroptosis by stabilizing SLC7A11 and promoting lipogenesis that dilutes membrane polyunsaturated fatty acids. This single signaling node thus couples apoptotic, oxidative, and metabolic resistance.
Metabolic reprogramming, specifically the Warburg shift toward aerobic glycolysis, also functions as a death-resistance strategy. By suppressing oxidative phosphorylation, cancer cells attenuate mitochondria-dependent and redox-sensitive death programs. This metabolic identity reduces TCA-cycle flux, limiting lipoylation-dependent cuproptosis, and dampens mitochondrial reactive oxygen species, which are required for ferroptotic lipid peroxidation. Consequently, the Warburg phenotype is not merely a biosynthetic adaptation for proliferation but a global strategy to insulate tumor cells from multiple forms of regulated death.
The immunological consequences of these death modalities vary significantly, with major implications for cancer therapy. Apoptosis is predominantly immunologically silent, packaging cellular contents to limit immune visibility. In contrast, lytic pathways such as pyroptosis, necroptosis, and cuproptosis release damage-associated molecular patterns (DAMPs) like calreticulin, HMGB1, and ATP. These signals activate dendritic cells and promote the cross-priming of tumor-antigen-specific CD8+ T lymphocytes, potentially converting immunologically cold tumors into those responsive to immune checkpoint blockade.
Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is particularly relevant in therapy-resistant mesenchymal cancer states. The review notes that cells undergoing epithelial-mesenchymal transition (EMT) are consistently more sensitive to ferroptosis. This sensitivity arises because EMT transcription factors like ZEB1 upregulate lipogenic enzymes that increase the pro-ferroptotic substrate load in membrane phospholipids. However, cancer cells employ extensive evasion mechanisms, including the upregulation of antioxidant defenses like GPX4 and FSP1, and the sequestration of polyunsaturated fatty acids in lipid droplets during cell-cycle arrest.
Cuproptosis, a recently characterized death modality, is centered in mitochondria and requires intact oxidative phosphorylation. It is triggered by copper-induced aggregation of lipoylated tricarboxylic acid cycle proteins, which overwhelms cellular proteostasis. Cancer cells evade cuproptosis primarily through the Warburg shift, which minimizes TCA-cycle flux and suppresses the lipoylation required for copper toxicity. Additionally, upregulation of copper efflux pumps like ATP7A and ATP7B, as well as glutathione-mediated chelation, further limit the mitochondrial accumulation of copper necessary for this death pathway.
Disulfidptosis represents another metabolically driven death process, coupling aberrant cystine import to catastrophic cytoskeletal disruption. It occurs in cells with high expression of the cystine/glutamate transporter SLC7A11 under conditions of glucose starvation. When the pentose phosphate pathway cannot regenerate sufficient NADPH to reduce imported cystine, disulfide bonds form across actin and cytoskeletal proteins, leading to rapid structural implosion. Tumors evade this by maintaining NADPH levels through alternative metabolic routes or by upregulating thioredoxin reductase to buffer disulfide stress.
The review identifies several principal barriers to the clinical translation of these insights. First, death sensitivity is context-dependent and dynamic, changing on therapeutic timescales due to epigenetic and transcriptional remodeling. Second, there is a scarcity of validated pharmacological probes for non-apoptotic pathways, limiting rigorous in vivo mechanism-of-action studies. For example, while ferroptosis inducers like erastin exist, their pharmacokinetic liabilities complicate clinical development. Third, the immunological consequences of non-apoptotic death in human tumors remain incompletely characterized and sometimes contradictory, clouding the clinical promise of immunogenic cell death combinations.
Emerging directions for therapeutic exploitation include proteolysis-targeting chimera (PROTAC)-based degradation of resistance nodes, such as RIPK1 or AKT, which may remove resistance proteins more completely than conventional kinase inhibition. The review also highlights the potential of composite multi-pathway death signatures and single-cell spatial approaches to resolve death competence at cellular resolution. By integrating these network-level perspectives, future therapies may move beyond single-pathway inducers toward combinations that collapse network redundancy and exploit the metabolic and signaling dependencies required for cancer survival.
The review details how specific molecular executors define each death modality, providing a mechanistic basis for targeted intervention. In pyroptosis, gasdermin D is cleaved by caspase-1 to form transmembrane pores approximately 10–20 nm in diameter, which disrupt osmotic integrity and permit the secretion of interleukin-1 beta and interleukin-18 before cell lysis. A distinct non-canonical route involves caspase-4, -5, and -11 directly sensing cytosolic lipopolysaccharide to cleave gasdermin D without caspase-1 involvement. Additionally, gasdermin E serves as an alternative executor with specific relevance to cancer; its cleavage by caspase-3 can convert otherwise silent apoptosis into inflammatory lysis. However, promoter methylation frequently silences gasdermin E in cancer cells, allowing caspase-3-mediated apoptosis to proceed without the inflammatory immune recruitment that would otherwise follow, thereby maintaining an immunologically cold tumor state.
Necroptosis is executed by the receptor-interacting protein kinase 3 and mixed lineage kinase domain-like protein axis, a process that is conditional rather than universal. Receptor-interacting protein kinase 1 functions context-dependently, acting as a scaffold for survival signaling in some settings and as a kinase promoting necroptosis in others. Cancer cells in colorectal, gastric, and pancreatic carcinomas often evade this pathway through transcriptional silencing or epigenetic repression of these key components. PANoptosis represents a convergent entity that engages pyroptotic, apoptotic, and necroptotic machinery simultaneously through scaffolded complexes called PANoptosomes. This integration provides redundancy, preventing the disruption of a single axis from conferring wholesale death resistance. Tumor necrosis factor alpha and interferon gamma can induce PANoptosis across diverse cancer cell lineages, linking inflammatory cytokines generated by successful immunotherapy to the elimination of therapy-resistant cancer populations.
Ferroptosis execution depends on the oxidative destruction of polyunsaturated fatty acid-containing phospholipids, a process driven by labile intracellular iron and reactive oxygen species. The endoplasmic reticulum is identified as the principal site where this peroxidation becomes lethal. Defense mechanisms include the glutathione peroxidase 4-glutathione axis, which reduces phospholipid hydroperoxides, as well as parallel systems involving ferroptosis suppressor protein 1 and coenzyme Q10. Because these systems operate through distinct mechanisms and compartments, cancer cells can shift their reliance when one is targeted, explaining the layered redundancy and incomplete in vivo responses to single-agent inhibition. Mesenchymal and epithelial-mesenchymal transition-associated cancer cells are consistently more sensitive to ferroptosis, a relationship linked to the upregulation of lipogenic enzymes that increase pro-ferroptotic substrate load in membrane phospholipids.
Disulfidptosis is triggered by the tension between cystine uptake and the capacity to reduce it. In cells with high expression of the cystine/glutamate transporter SLC7A11, glucose starvation collapses pentose phosphate pathway activity, depleting NADPH. This prevents the reduction of imported cystine, leading to the accumulation of disulfide bonds across F-actin and cytoskeletal proteins. The resulting collapse of F-actin networks causes rapid structural implosion, distinct from apoptotic blebbing or necroptotic organelle swelling. CRISPR-based screens have shown that inactivation of the WAVE regulatory complex suppresses disulfidptosis, whereas constitutive activation of Rac1 enhances it, indicating that cytoskeletal architecture is a functional determinant of execution. Tumors may also evade this death by outcompeting tumor-infiltrating CD8+ T lymphocytes for extracellular cystine, inducing T-cell exhaustion while remaining protected through adequate glucose metabolism.
Parthanatos is a regulated necrotic death driven by poly ADP-ribose polymerase-1 hyperactivation after extensive DNA damage. This hyperactivation generates long, branched poly-ADP-ribose chains, consuming NAD+ and ATP until energy stores become incompatible with viability. The resulting poly-ADP-ribose chains translocate to mitochondria, releasing apoptosis-inducing factor into the nucleus to cause large-scale DNA fragmentation without caspase activation. This modality is particularly relevant in breast cancer susceptibility gene 1 or 2-deficient tumors, where poly ADP-ribose polymerase inhibitor-induced synthetic lethality engages parthanatic execution when lesions are extensive and unresolvable. Cancer cells evade this death by overexpressing poly ADP-ribose glycohydrolase, which removes poly-ADP-ribose before it reaches the threshold for mitochondrial apoptosis-inducing factor release, or by upregulating NAD+ biosynthetic enzymes to replenish energy stores.
Lysosomal cell death is initiated by lysosomal membrane permeabilization, which releases cathepsins and other hydrolases into the cytoplasm. These enzymes can cleave Bid to activate caspases or cause caspase-independent death through mitochondrial damage. This pathway can bypass the BCL-2 family checkpoint governing mitochondrial apoptosis, meaning cells with high BCL-2 or BCL-XL expression that resist direct BH3-mimetic therapy may remain sensitive to lysosomal death. Resistance involves heat shock protein 70, which stabilizes lysosomal membranes, and transcription factor EB-driven lysosomal biogenesis, which expands a redundant compartment able to buffer focal permeabilization. Entosis, another non-canonical modality, involves a viable cell invading and being internalized by another, forming an entotic vacuole. The inner cell may subsequently die through host-cell lysosomal degradation, a process positively regulated by p53 through RhoA-Rho-associated coiled-coil-containing protein kinase-dependent contractility.
The tumor microenvironment actively shapes death sensitivity through non-cell-autonomous mechanisms. Cancer-associated fibroblasts secrete exosome-derived microRNAs that target ACSL4, suppressing polyunsaturated fatty acid enrichment in pancreatic cancer cells and conferring gemcitabine resistance. Conversely, interferon gamma from activated CD8+ T cells downregulates SLC7A11 through interferon regulatory factor 1, sensitizing cancer cells to ferroptosis. This creates a positive adaptive-immunity-ferroptosis feedback loop, providing a rationale for combining ferroptosis inducers with immune checkpoint blockade. However, ferroptosis can also be immunosuppressive; oxidized phospholipids can activate peroxisome proliferator-activated receptor gamma in macrophages, promoting an immunosuppressive M2-like phenotype. Furthermore, PD-1 signaling directly promotes ferroptosis in tumor-infiltrating CD8+ T cells by suppressing phospholipid phosphatase 1, meaning checkpoint blockade releases cytotoxic T lymphocyte effector function while protecting them from ferroptotic bystander death.
Epigenetic plasticity enables cancer cells to switch resistance states on therapeutic timescales. Promoter methylation silences gasdermin E, uncoupling caspase-3 activation from pyroptotic inflammation, a state reversible with DNA methyltransferase or histone deacetylase inhibitors. H3K27me3-mediated repression of RIPK3 in colorectal and pancreatic cancers silences necroptotic execution and is reversible with EZH2 inhibition. Non-coding RNAs also regulate death sensitivity post-transcriptionally, with microRNA and long non-coding RNA species targeting GPX4, SLC7A11, ACSL4, and RIPK3 differentially expressed in drug-resistant cells. Cancer stem cells contribute to resistance through high BCL-2 and MCL-1 expression, constitutive NRF2 activity, and predominantly glycolytic metabolism. Targeting carnitine palmitoyltransferase 1A in lung cancer overcame cancer stem cell-mediated ferroptosis resistance by increasing membrane polyunsaturated fatty acids and depleting antioxidant capacity, synergizing with anti-PD-1 therapy.
Subject of Research: Network-level mechanisms of cancer resistance to regulated cell death
Article Title: Death plasticity in cancer: a network perspective on regulated cell death pathways and their therapeutic exploitation
Article References: Bülbül, M. V., & Demircan, T. (2026). Death plasticity in cancer: a network perspective on regulated cell death pathways and their therapeutic exploitation. Pathology & Oncology Research, 32, Article 1612568. https://doi.org/10.3389/pore.2026.1612568
Image Credits: AI Generated
DOI: 10.3389/pore.2026.1612568
Keywords: cancer, regulated cell death, ferroptosis, apoptosis, cuproptosis, disulfidptosis, pyroptosis, necroptosis, tumor microenvironment, drug resistance, Death, plasticity
