Pathway Atlas

EMT and metastatic invasion

EMT is a cellular program in which epithelial cells acquire mesenchymal characteristics, enhancing motility and invasiveness. In cancer, EMT contributes to metastasis, therapy resistance, and stem-like properties. EMT is metabolically demanding and often associated with shifts toward oxidative metabolism and enhanced stress tolerance.

Neutrophil / MPO / NETs

Neutrophils contribute to tumor progression through release of MPO, reactive oxygen species, proteases, and neutrophil extracellular traps (NETs). NETs can capture circulating tumor cells and facilitate metastatic seeding. Tumor-associated neutrophils often adopt a pro-tumorigenic phenotype that enhances inflammation, angiogenesis, immune suppression, and dissemination.

Integrin–FAK–Src signaling (focal adhesion)

Integrins are transmembrane receptors that connect the ECM to intracellular cytoskeletal and signaling networks. In cancer, integrin signaling activates FAK/Src pathways, promoting survival, migration, and resistance to anoikis. This axis links mechanical cues from the microenvironment to proliferative and metabolic signaling programs.

Angiogenesis / VEGF / HIF-1α

Angiogenesis is the formation of new blood vessels, largely driven by VEGF signaling, and it is strongly induced by hypoxia via stabilization of HIF-1α. In cancer, angiogenesis is a structural adaptation that expands oxygen/nutrient delivery, supports tumor growth beyond diffusion limits, and creates abnormal, leaky vasculature that facilitates invasion and metastatic dissemination. The VEGF/HIF axis also reshapes the microenvironment—promoting immunosuppressive cell trafficking and creating heterogeneous oxygen gradients that reinforce therapy resistance.

COX-2 / PGE₂

Cyclooxygenase-2 (COX-2) catalyzes conversion of arachidonic acid into prostaglandins, most notably prostaglandin E₂ (PGE₂), a potent inflammatory and pro-tumorigenic lipid mediator. In cancer, COX-2 upregulation increases PGE₂ production, which promotes proliferation, angiogenesis, immune suppression, epithelial–mesenchymal transition, and metastatic behavior. PGE₂ signaling through EP receptors also enhances myeloid skewing and dampens cytotoxic T-cell activity, making this axis a central inflammation-to-progression amplifier within the tumor microenvironment.

Eicosanoids

Eicosanoids are bioactive lipid mediators derived from arachidonic acid via COX and LOX enzymes, producing prostaglandins and leukotrienes. In cancer, elevated prostaglandin E2 (PGE2) promotes proliferation, angiogenesis, immune suppression, and metastatic behavior. Chronic activation of eicosanoid signaling links inflammation to tumor progression and represents a key interface between lipid metabolism and the tumor microenvironment.

NF-κB / TNF-α / IL-6 inflammatory axis

The NF-κB axis is a central inflammatory transcription program activated by cytokines such as TNF-α and by stress/injury signals, driving expression of survival genes, adhesion molecules, and additional cytokines that amplify inflammation. In cancer, chronic TNF-α → NF-κB signaling and IL-6 feed-forward loops remodel the tumor microenvironment toward immunosuppression, angiogenesis, and invasive behavior while directly protecting tumor cells from apoptosis. This pathway is a classic “inflammation-to-progression” engine: it sustains pro-growth signaling under stress and enables metastatic competence through persistent inflammatory conditioning.

Cancer stemness (CD44, ALDH, Nanog/Sox2)

Cancer stemness refers to a subpopulation of tumor cells characterized by self-renewal, tumor-initiating capacity, and resistance to therapy, often marked by CD44, ALDH activity, and transcription factors such as Nanog and Sox2. These stem-like cells exhibit transcriptional and metabolic plasticity that allows adaptation to hypoxia, nutrient stress, and cytotoxic exposure. Persistence of this compartment underlies relapse, metastatic colonization, and long-term disease propagation.

Aerobic glycolysis (Warburg effect)

Warburg glycolysis refers to the preferential use of aerobic glycolysis in cancer cells, where glucose is converted to lactate even in the presence of oxygen. While less efficient for ATP per molecule of glucose, this metabolic configuration enables rapid generation of glycolytic intermediates that feed biosynthetic pathways. In cancer, the Warburg effect supports biomass expansion, acidifies the tumor microenvironment, and promotes immune evasion and invasion.

Glycogen metabolism

Glycogen metabolism regulates storage and mobilization of glucose as glycogen. Some tumors accumulate glycogen as a metabolic reserve that can be mobilized during hypoxia or nutrient scarcity. Glycogen breakdown supports glycolysis and redox balance under stress, enhancing tumor survival during fluctuating nutrient availability.

Glycolytic Branching

Glycolytic branch pathways divert intermediates from core glycolysis into biosynthetic routes such as serine synthesis, glycerol-3-phosphate production, and hexosamine biosynthesis. These branching points transform glucose from a pure energy source into a structural carbon backbone for lipids, nucleotides, and glycoproteins. In cancer, upregulation of branching enzymes increases anabolic flexibility and allows tumor cells to dynamically allocate glucose toward growth and survival needs.

Hexosamine/HBP

The hexosamine pathway diverts a small fraction of glucose into production of UDP-GlcNAc, which is used for protein O-GlcNAcylation and glycosylation. This modification acts as a nutrient-sensing regulatory system, altering transcription factors, signaling proteins, and metabolic enzymes. In cancer, increased HBP flux enhances stress tolerance, stabilizes oncogenic signaling networks, and supports growth under fluctuating nutrient conditions.

Lactate transport (MCT1/4 shuttle)

The lactate shuttle describes export and import of lactate via monocarboxylate transporters (MCT4 typically exports; MCT1 can import). In tumors, lactate is not merely waste — it functions as a fuel for oxidative cancer cells and stromal components, enabling metabolic symbiosis within the tumor microenvironment. Elevated lactate also promotes angiogenesis, immune suppression, and metastatic potential.

Pentose Phosphate Pathway (PPP)

The Pentose Phosphate Pathway branches from glycolysis to generate ribose-5-phosphate (for nucleotide synthesis) and NADPH (for reductive biosynthesis and antioxidant defense). In cancer, PPP activation supports both rapid DNA production and protection against oxidative damage. It functions as a glucose-axis amplifier, converting glycolytic input into anabolic and redox advantages that reinforce tumor growth and therapy resistance.

Ether lipids / plasmalogens

Ether lipids, including plasmalogens, are specialized membrane lipids synthesized partly in peroxisomes. Many cancers exhibit elevated ether lipid synthesis, which enhances membrane integrity, signaling capacity, and resistance to oxidative stress. Altered plasmalogen content can influence tumor aggressiveness and modulate ferroptosis susceptibility.

Fatty acid uptake and trafficking

Fatty acid uptake pathways regulate import of circulating lipids via transporters such as CD36 and FATP family proteins. Many tumors increase reliance on exogenous fatty acids, particularly in lipid-rich environments (e.g., adipose tissue or liver metastases). Enhanced lipid uptake supports membrane synthesis, β-oxidation, and signaling lipid production, contributing to metastatic fitness and therapy resistance.

Glycerol-3-phosphate and lipid synthesis

Glycerol-3-phosphate (G3P) provides the structural backbone for triglycerides and phospholipids. Derived from glycolytic intermediates, G3P links glucose metabolism to membrane and lipid droplet formation. In cancer, enhanced G3P availability facilitates rapid phospholipid synthesis for cell division and supports lipid remodeling under metabolic stress.

Glycerophospholipid remodeling (Lands’ Cycle)

The Lands’ cycle remodels membrane phospholipids by replacing fatty acyl chains, altering membrane composition and signaling properties. In cancer, dynamic phospholipid remodeling influences membrane fluidity, receptor organization, and susceptibility to lipid peroxidation. This pathway contributes to both growth signaling optimization and modulation of ferroptosis sensitivity.

Lipogenesis

De novo lipogenesis converts acetyl-CoA into fatty acids required for membrane synthesis, signaling lipids, and energy storage. Many cancers upregulate enzymes such as FASN and ACC to maintain membrane expansion during rapid proliferation. Increased lipogenesis also contributes to therapy resistance and supports membrane composition changes that favor oncogenic signaling.

FASN / SREBP-1c-driven lipogenesis

FASN / SREBP-1c-driven lipogenesis is a metabolic programme in which sterol regulatory element-binding protein 1c (SREBP-1c) activates fatty-acid synthesis genes, including fatty acid synthase (FASN), enabling cells to convert acetyl-CoA into newly synthesized fatty acids. In cancer, persistent activation of this axis supplies membrane lipids and signalling intermediates needed for rapid proliferation while supporting metabolic adaptation, invasion, metastasis and treatment resistance; elevated SREBP-1/FASN activity is therefore a common feature of lipogenically reprogrammed tumours and a potential therapeutic vulnerability.

Membrane lipid rafts (cholesterol-rich domains)

Membrane rafts are cholesterol-enriched microdomains that organize signaling receptors and downstream effectors. In cancer cells, raft stabilization enhances growth factor signaling, receptor clustering, and pro-survival pathway activation. Altered membrane composition can therefore amplify oncogenic signaling intensity and contribute to resistance mechanisms.

Mevalonate pathway and cholesterol synthesis

The mevalonate pathway produces cholesterol and isoprenoid intermediates required for membrane integrity and protein prenylation. In cancer, increased mevalonate flux supports membrane raft formation and activation of oncogenic proteins such as RAS and RHO via prenylation. Dysregulation of this pathway enhances proliferation, invasion, and survival signaling.

Amino acid transport and protein synthesis

Amino acid transporters regulate uptake of essential and non-essential amino acids required for protein synthesis and metabolic signaling. Many cancers overexpress transporters such as LAT1 (SLC7A5) to sustain high translation rates and mTOR activation. Enhanced amino acid influx supports rapid biomass accumulation and maintains signaling pathways that reinforce growth and survival.

Arginine metabolism (polyamines and nitric oxide)

Arginine metabolism generates polyamines (putrescine, spermidine, spermine) and nitric oxide (NO), both of which influence proliferation and signaling. Polyamines stabilize DNA structure, promote transcription, and support rapid cell division, while NO can modulate angiogenesis and immune interactions. Many cancers upregulate arginine utilization and polyamine synthesis to sustain growth and reshape the tumor microenvironment.

Aspartate / Asparagine axis

Aspartate and asparagine serve as nitrogen carriers and precursors for nucleotide and protein synthesis. In cancer, asparagine availability influences protein translation, stress adaptation, and metastatic behavior, particularly under glutamine limitation. Regulation of this axis enables tumor cells to buffer amino acid scarcity and maintain proliferative signaling.

Aspartate/malate shuttles

The aspartate–malate shuttle transfers reducing equivalents (NADH) from the cytosol into mitochondria, maintaining redox balance while enabling continued glycolysis. In proliferating cancer cells, this shuttle is critical for sustaining NAD⁺ regeneration and supporting aspartate production, a key precursor for nucleotide synthesis. Disruption of shuttle function limits proliferation by constraining both redox equilibrium and biomass generation.

Glutamine-driven TCA anaplerosis

Glutamine-driven anaplerosis refers specifically to replenishment of TCA cycle intermediates (particularly α-ketoglutarate) using glutamine-derived carbon. In cancer cells, this maintains mitochondrial output even when glycolytic flux is high (Warburg phenotype), preserving biosynthetic precursor supply for lipids, nucleotides, and non-essential amino acids. This pathway is critical for metabolic flexibility, allowing tumor cells to survive nutrient fluctuation and therapeutic stress.

Glutaminolysis

Glutaminolysis is the metabolic conversion of glutamine into glutamate and then α-ketoglutarate, feeding carbon into the TCA cycle while also supporting redox balance and biosynthesis. In cancer, especially highly proliferative tumors, glutaminolysis acts as a parallel fuel system to glucose, sustaining ATP production and providing nitrogen for nucleotide and amino acid synthesis. It also supports NADPH generation indirectly, helping tumor cells buffer oxidative stress and maintain anabolic momentum.

Nucleotide synthesis (purines and pyrimidines)

De novo purine and pyrimidine synthesis provides the building blocks for DNA and RNA replication. Tumor cells dramatically increase nucleotide synthesis to sustain continuous cell division, often coupling it to glutamine metabolism, PPP activity, and one-carbon flux. Disruption of this pathway constrains replication capacity and can induce replication stress, making it a central “biomass bottleneck” in proliferative cancers.

Polyamine synthesis

Polyamine synthesis converts ornithine into putrescine, spermidine, and spermine through enzymes such as ornithine decarboxylase (ODC). Polyamines stabilize DNA, regulate transcription, and promote cell cycle progression. Many cancers upregulate ODC and related enzymes, increasing proliferative capacity and enhancing tumor growth.

Serine–Glycine / One-Carbon (1C) metabolism

The serine–glycine–one-carbon network channels carbon units into folate-dependent reactions that drive nucleotide synthesis, methylation reactions, and redox control (via NADPH generation). In cancer, upregulated serine synthesis and 1C flux directly support rapid DNA/RNA production and epigenetic remodeling. This pathway tightly links amino acid availability to proliferation rate and transcriptional plasticity.

Urea cycle and arginine flux

The urea cycle detoxifies ammonia by converting it to urea while interconverting arginine, citrulline, and ornithine. In cancer, partial dysregulation of the urea cycle can redirect nitrogen toward nucleotide and polyamine synthesis instead of disposal. Some tumors become auxotrophic for arginine due to loss of key enzymes (e.g., ASS1), creating metabolic vulnerabilities.

NADPH production and redox balance

The Redox/NADPH axis encompasses pathways that generate and utilize NADPH to maintain cellular antioxidant systems, including glutathione and thioredoxin. Cancer cells experience chronic oxidative stress due to high metabolic flux, oncogenic signaling, and mitochondrial activity, making NADPH production essential for survival. Sustained NADPH supply enables tumor cells to buffer reactive oxygen species (ROS), resist therapy-induced oxidative damage, and preserve anabolic metabolism.

NRF2–GSH redox axis

NRF2 is a master transcriptional regulator of antioxidant defense that increases expression of genes involved in glutathione synthesis, NADPH regeneration, detoxification enzymes, and redox buffering. In cancer, NRF2 activation (via KEAP1 loss, oxidative stress, or oncogenic signaling) creates a high-capacity “redox shield” that supports survival under ROS-generating metabolism and protects against chemo/radiation-induced oxidative injury. This axis also stabilizes metabolic flexibility by preserving thiol redox balance, directly influencing ferroptosis sensitivity and stress tolerance.

Autophagy and lysosomal system

Autophagy is a cellular recycling process that degrades damaged organelles and macromolecules through lysosomal digestion, returning nutrients to the cytosol. In cancer, autophagy can act as a stress-adaptation mechanism, allowing tumor cells to survive nutrient deprivation, hypoxia, and therapy-induced damage. By maintaining intracellular nutrient pools and mitochondrial quality, autophagy supports long-term tumor persistence and metabolic resilience.

Fatty acid β-oxidation (FAO)

Fatty acid oxidation breaks down fatty acids in mitochondria to generate acetyl-CoA, NADH, and FADH₂ for ATP production. In cancer, FAO supports survival during glucose limitation and can fuel metastasis, stemness, and resistance to oxidative stress. Tumors that activate FAO often display enhanced metabolic flexibility and adaptation to hostile microenvironments.

Mitochondrial Electron Transport Chain (ETC I–V)

The mitochondrial electron transport chain (ETC) transfers electrons through complexes I–IV to generate a proton gradient used by complex V (ATP synthase) to produce ATP. While glycolysis is elevated in many tumors, mitochondrial respiration often remains active and supports biosynthesis, redox control, and metabolic flexibility. Alterations in ETC function influence ROS production, apoptotic sensitivity, and resistance to metabolic therapies.

Mitochondrial biogenesis

Mitochondrial biogenesis is the coordinated expansion of mitochondrial mass, mtDNA content, and respiratory capacity through activation of nuclear and mitochondrial transcription programs. In cancer, increased mitochondrial biogenesis enhances oxidative phosphorylation, metabolic flexibility, and resistance to energetic or oxidative stress. Tumors capable of dynamically increasing mitochondrial content often exhibit improved survival during therapy, metastatic dissemination, and adaptation to nutrient-variable microenvironments.

Mitochondrial pyruvate import and TCA cycle

This pathway governs transport of pyruvate into mitochondria and its conversion to acetyl-CoA for entry into the TCA cycle. Although cancer cells exhibit high glycolysis, many tumors retain active mitochondrial oxidation to sustain biosynthesis and redox control. Regulation of mitochondrial pyruvate import balances glycolytic versus oxidative metabolism and determines metabolic plasticity under therapeutic or nutrient stress.

Mitophagy and mitochondrial quality control

Mitophagy is the selective autophagic removal of damaged or dysfunctional mitochondria, preserving mitochondrial quality and preventing excessive ROS accumulation. In cancer, mitophagy supports survival under metabolic stress by maintaining an efficient mitochondrial pool and preventing apoptosis triggered by mitochondrial damage. By fine-tuning mitochondrial turnover, tumor cells preserve bioenergetic capacity and resistance to oxidative injury.

PGC-1α (mitochondrial biogenesis regulator)

PGC-1α is a transcriptional coactivator that coordinates mitochondrial biogenesis and oxidative metabolism by activating nuclear respiratory factors and mitochondrial transcription programs. In cancer, PGC-1α expression can enhance oxidative phosphorylation, antioxidant defense, and metastatic fitness, particularly in cells adapting to energetic or oxidative stress. As a regulatory node, PGC-1α integrates metabolic state with transcriptional control of mitochondrial mass and respiratory capacity.

BCAA/mTOR

BCAAs (leucine, isoleucine, valine) activate mTORC1, a master regulator of protein synthesis and cell growth. In cancer, elevated BCAA uptake and metabolism stimulate anabolic signaling, enhance translation capacity, and coordinate nutrient availability with proliferation. Persistent mTOR activation drives tumor expansion and can confer resistance to metabolic stress.

Cell cycle checkpoints (CDK4/6–RB–E2F, G1/S, G2/M)

Cell cycle checkpoints regulate progression through G1/S and G2/M phases via cyclins and cyclin-dependent kinases (CDKs). In cancer, dysregulation of CDKs permits uncontrolled proliferation despite DNA damage or metabolic stress. Targeting checkpoint control can expose tumor reliance on hyperactive cell division machinery.

EGFR / HER-family signaling

The epidermal growth factor receptor (EGFR/HER) family comprises receptor tyrosine kinases that activate downstream proliferative and survival pathways upon ligand binding or amplification. In cancer, EGFR overexpression or mutation drives persistent signaling through PI3K–AKT and MAPK cascades, enhancing glucose uptake, protein synthesis, and resistance to apoptosis. Dysregulated HER-family signaling also promotes invasion, angiogenesis, and therapeutic resistance through sustained growth factor signaling loops.

Hedgehog (SHH/GLI)

Hedgehog signaling is initiated by Sonic Hedgehog (SHH) ligand binding, relieving inhibition of Smoothened and enabling GLI transcription factors to activate developmental gene programs. In cancer, aberrant Hedgehog signaling promotes proliferation, stem cell maintenance, and stromal activation, particularly in tumors with strong epithelial–stromal crosstalk. GLI-mediated transcription enhances survival pathways and contributes to therapy resistance and metastatic progression.

Hippo / YAP–TAZ

The Hippo pathway restricts cell growth by phosphorylating and inhibiting the transcriptional coactivators YAP and TAZ. When Hippo signaling is suppressed, YAP/TAZ translocate to the nucleus and activate genes promoting proliferation, survival, mechanotransduction, and stemness. In cancer, dysregulated YAP/TAZ activity integrates mechanical cues from the extracellular matrix with metabolic and growth signals, driving tumor progression, therapy resistance, and metastatic competence.

JAK/STAT (STAT3)

The JAK/STAT pathway transduces signals from cytokine receptors to the nucleus, where STAT transcription factors regulate genes involved in proliferation, survival, and immune modulation. Persistent STAT3 activation—often downstream of IL-6 or growth factor signaling—is common in cancer and promotes anti-apoptotic gene expression, angiogenesis, and immunosuppressive cytokine production. STAT3 acts as a convergence node linking inflammation, tumor cell intrinsic survival programs, and microenvironmental conditioning.

Notch

Notch signaling is activated through cell–cell contact, leading to proteolytic release of the Notch intracellular domain (NICD), which translocates to the nucleus to regulate differentiation and lineage commitment genes. In cancer, aberrant Notch activation supports stemness, survival, angiogenesis, and resistance to therapy, often in a context-dependent manner. Notch also shapes tumor–stroma interactions, influencing immune infiltration and maintaining hierarchical tumor organization.

PI3K–AKT–mTOR (signaling)

The PI3K/AKT/mTOR pathway integrates growth factor signals with nutrient availability to regulate protein synthesis, glucose uptake, and cell survival. In cancer, constitutive activation of this axis drives anabolic metabolism, increases glycolysis, and enhances resistance to apoptosis. Persistent mTOR signaling coordinates nutrient sensing with proliferation, reinforcing tumor growth even under metabolic stress.

RAS–RAF–MEK–ERK (MAPK)

The RAS–RAF–MEK–ERK cascade is a central mitogenic signaling pathway transmitting extracellular growth signals to nuclear transcription programs. Oncogenic mutations in RAS or RAF result in constitutive pathway activation, driving proliferation, metabolic reprogramming, and survival independent of upstream cues. MAPK signaling enhances glycolysis, nucleotide synthesis, and cell-cycle progression, tightly linking growth signaling to metabolic expansion in cancer.

TGF-β / SMAD signaling

Transforming growth factor-β (TGF-β) signals through SMAD transcription factors to regulate cell differentiation, immune modulation, and extracellular matrix remodeling. In early tumorigenesis, TGF-β can suppress proliferation, but in established cancers it frequently promotes epithelial–mesenchymal transition, invasion, immune evasion, and metastatic progression. This pathway integrates stromal and inflammatory cues, functioning as a context-dependent regulator of tumor plasticity.

Wnt / β-catenin

Wnt signaling stabilizes β-catenin, allowing it to translocate to the nucleus and activate transcriptional programs controlling proliferation, stemness, and cell fate determination. In cancer, constitutive Wnt/β-catenin activation drives uncontrolled proliferation, maintains cancer stem cell compartments, and promotes immune exclusion by altering cytokine and chemokine profiles. This pathway is especially central in colorectal tumorigenesis, where APC loss or β-catenin stabilization establishes a foundational growth program early in disease development.

Epigenetic regulation and transcriptional control

Epigenetic regulation controls gene expression through chromatin state (DNA methylation, histone modifications, nucleosome positioning) and transcription-factor access, without changing DNA sequence. In cancer, epigenetic drift and rewiring enable persistent activation of growth/survival programs, suppression of differentiation, and rapid phenotypic switching under stress (including therapy exposure). Because epigenetic enzymes depend on metabolic cofactors (e.g., SAM, acetyl-CoA, α-KG), this layer acts as a “state controller” that translates nutrient/redox context into durable transcriptional programs.

Methionine cycle and methylation capacity (SAM/SAH)

Methionine metabolism generates S-adenosylmethionine (SAM), the universal methyl donor for DNA, RNA, and histone methylation. Cancer cells often exhibit increased methionine dependence to sustain epigenetic remodeling and transcriptional plasticity. Alterations in this pathway affect gene expression programs that regulate proliferation, differentiation, and resistance to stress.

NF-κB/RELA functional conversion

NF-κB/RELA functional conversion describes the context-dependent shift of the NF-κB subunit RELA/p65 between transcriptional programs that suppress malignant transformation or promote tumor survival and progression. In cancer, cooperating mutations, altered chromatin states, post-translational modifications, and microenvironmental signals can redirect RELA toward pro-inflammatory, anti-apoptotic, proliferative, invasive, and therapy-resistant gene expression. This functional plasticity means that RELA activity is not uniformly oncogenic, and its biological effect depends strongly on tumor genotype, cellular lineage, and signalling context.

Cellular senescence and SASP

Cellular senescence is a stable cell-cycle arrest triggered by oncogenic stress or DNA damage, mediated by p53/p21 and p16/RB pathways. While initially tumor-suppressive, senescent cells secrete a pro-inflammatory secretome known as the senescence-associated secretory phenotype (SASP). In established cancers, SASP factors promote angiogenesis, immune modulation, and tissue remodeling, converting a protective mechanism into a pro-tumorigenic driver.

ER stress and unfolded protein response (UPR)

The unfolded protein response is activated by accumulation of misfolded proteins in the ER and signals through PERK, IRE1α, and ATF6. These pathways initially restore proteostasis but can induce apoptosis if stress is excessive. In cancer, chronic UPR activation supports adaptation to hypoxia and metabolic stress, sustaining survival under hostile microenvironmental conditions.

Ubiquitin–proteasome system (UPS)

The ubiquitin–proteasome system degrades misfolded, damaged, or regulatory proteins, maintaining proteostasis. Cancer cells rely on heightened proteasomal activity to manage increased protein synthesis and oncogenic stress. Disruption of proteasome function can trigger accumulation of toxic proteins and apoptosis.

Ferroptosis (execution / cell death)

Ferroptosis is a regulated cell death program driven by iron-dependent lipid peroxide accumulation that catastrophically damages cellular membranes. Its execution phase occurs when lipid peroxidation overwhelms detox capacity, leading to loss of membrane integrity and bioenergetic collapse (distinct from apoptosis and necroptosis). In cancer, ferroptosis matters because many tumors sit near a threshold: high ROS pressure, iron loading, and PUFA-rich membranes increase risk, while upregulated antioxidant defenses (GPX4/GSH, NRF2 programs) suppress execution—making ferroptosis both a vulnerability and an escape route depending on redox state.

(1) PUFA-enriched membrane lipids

Polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids create substrates that are highly susceptible to peroxidation. In cancer, increased PUFA incorporation can enhance membrane fluidity and signaling but also creates vulnerability to lipid peroxidation under oxidative stress. The abundance and distribution of PUFA-containing phospholipids are therefore key determinants of ferroptosis sensitivity.

(2) GPX4 / GSH axis (lipid peroxide detox)

Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides to non-toxic lipid alcohols using glutathione as a cofactor. This detoxification system prevents accumulation of lethal lipid peroxides and is a central suppressor of ferroptosis. Many cancers upregulate GPX4 and glutathione synthesis to protect against oxidative stress and maintain membrane integrity.

(3) Iron handling and labile iron pool

Intracellular iron homeostasis regulates the size of the labile iron pool, which participates in Fenton reactions that generate lipid-damaging radicals. Cancer cells often increase iron uptake and storage to support DNA synthesis and mitochondrial activity. However, elevated redox-active iron also increases susceptibility to ferroptosis when antioxidant defenses are compromised.

Ceramide/S1P

Ceramide and S1P are bioactive sphingolipids with opposing cellular effects: ceramide promotes apoptosis, whereas S1P promotes proliferation and survival. Cancer cells often shift sphingolipid metabolism toward S1P dominance, suppressing apoptotic signaling. This “sphingolipid rheostat” influences cell fate decisions, angiogenesis, and metastatic progression.

Cuproptosis

Cuproptosis is a recently described copper-dependent regulated cell death pathway linked to mitochondrial TCA cycle activity. Excess copper binds lipoylated TCA enzymes, triggering protein aggregation and proteotoxic stress. Tumors with high mitochondrial respiration may exhibit distinct sensitivity to copper-mediated toxicity, highlighting a metal–metabolism interface separate from ferroptosis and apoptosis.

DNA damage and repair / PARP

The DNA damage response (DDR) is a network of sensing and repair pathways that detect genomic lesions and coordinate repair, cell cycle arrest, or apoptosis. Cancer cells often experience high replication stress and rely heavily on DDR pathways (e.g., ATM, ATR, PARP) to survive genomic instability. This dependency creates therapeutic vulnerabilities but also enables resistance through enhanced repair capacity.

Extrinsic apoptosis (death receptors)

Extrinsic apoptosis is initiated by activation of death receptors such as Fas (CD95), TRAIL receptors (DR4/DR5), or TNF receptor family members upon ligand binding. Receptor engagement recruits adaptor proteins and activates caspase-8, triggering a proteolytic cascade that dismantles the cell. In cancer, resistance frequently arises through reduced death receptor expression or increased anti-apoptotic signaling, allowing evasion of immune-mediated cytotoxicity.

Intrinsic apoptosis (mitochondrial / Bcl-2)

The intrinsic apoptotic pathway is governed by mitochondrial outer membrane permeabilization and regulated by BCL-2 family proteins. Cancer cells frequently upregulate anti-apoptotic proteins (e.g., BCL-2, BCL-XL) to evade programmed cell death. Suppression of intrinsic apoptosis allows survival despite oncogenic stress, DNA damage, or metabolic imbalance.

Lipid peroxidation (membrane oxidative damage)

Lipid peroxidation is the oxidative modification of polyunsaturated fatty acids within cellular membranes, generating reactive lipid radicals and aldehydes that disrupt membrane integrity. In cancer, elevated metabolic flux and ROS production increase susceptibility to membrane oxidative damage, which can impair signaling platforms and organelle function. When lipid peroxide accumulation exceeds detox capacity, it contributes to cell death pathways—including but not limited to ferroptosis—making membrane oxidative stress a critical vulnerability node.

Replication stress / checkpoint signaling

Replication stress arises when DNA replication machinery encounters obstacles such as nucleotide depletion or oncogene activation. Cancer cells often operate under chronic replication stress and depend on ATR/CHK1-mediated signaling to prevent catastrophic DNA damage. This pathway enables continued proliferation despite genomic instability.

Immune checkpoints and myeloid skewing (M2/MDSC)

Immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4 attenuate T-cell activation, enabling tumors to evade immune surveillance. Concurrently, tumor-derived cytokines and metabolites promote polarization of macrophages toward an M2 phenotype and expansion of myeloid-derived suppressor cells (MDSCs), which further suppress cytotoxic immunity. This combined checkpoint–myeloid axis restructures the tumor microenvironment into an immunosuppressive niche that supports angiogenesis, invasion, and therapeutic resistance.

Tryptophan/Kynurenine

The kynurenine pathway metabolizes tryptophan into immunomodulatory metabolites, including kynurenine, through enzymes such as IDO1 and TDO2. In cancer, increased tryptophan catabolism suppresses anti-tumor immune responses by impairing T-cell function and promoting regulatory T-cell activity. This pathway represents a metabolic-immune interface that enables tumors to evade immune surveillance.

Tryptophan–kynurenine axis (IDO/TDO)

Indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step in tryptophan degradation to kynurenine. In tumors, elevated IDO/TDO activity depletes local tryptophan and accumulates kynurenine metabolites that suppress effector T-cell proliferation while promoting regulatory T cells. This axis establishes metabolic immune tolerance, directly linking amino acid metabolism to immune escape and checkpoint resistance.

ENT1 inhibition / Adenosinergic signalling

ENT1 inhibition / adenosinergic signalling describes modulation of cellular adenosine transport through equilibrative nucleoside transporter 1 (ENT1/SLC29A1), which alters the balance between extracellular receptor-mediated signalling and intracellular adenosine metabolism. In cancer, reduced ENT1 activity can increase extracellular adenosine and reinforce A2A/A2B receptor-mediated immune suppression, invasion, and treatment resistance; however, ENT1 blockade in activated T cells may conversely prevent intracellular adenosine-induced metabolic suppression and restore antitumor cytotoxicity. The oncological effect is therefore strongly compartment-dependent, varying according to whether ENT1 is inhibited in tumor cells, stromal cells, or effector lymphocytes.

MHC-I / antigen-presentation restoration

MHC-I antigen-presentation restoration is the reactivation of the cellular machinery that processes intracellular proteins into peptides and displays them on major histocompatibility complex class I (MHC-I; HLA-I in humans) molecules at the tumor-cell surface. In cancer, loss or suppression of this pathway allows malignant cells to evade recognition by cytotoxic CD8+ T cells and can contribute to resistance to immune-checkpoint therapy; restoring MHC-I expression and peptide presentation can therefore increase tumor immunogenicity and re-establish T-cell-mediated immune surveillance.