{"slug":"mechanism","tag":"mechanism","variants":["mechanism"],"description":"Pathways and ideas that explain how a cancer process works rather than a single product.","count":85,"kinds":{"pathway":68,"idea":17},"related":[{"slug":"mechanics-atlas","tag":"mechanics-atlas","shared":37},{"slug":"open-question","tag":"open-question","shared":17},{"slug":"theory","tag":"theory","shared":1}],"records":[{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","route":"/pathways/metastatic-cascade/","tldr":"How cancer spreads: cells leave the tumour, squeeze into blood or lymph vessels, survive the journey, exit into a new organ, often sleep there for years, and finally grow. Metastasis causes about 90% of cancer deaths."},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/","tldr":"A tumour is not just cancer cells. It is a neighbourhood of fibroblasts, immune cells, blood vessels, nerves, and scaffolding that the cancer recruits and corrupts, and that decides whether drugs and immune cells can get in."},{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/","tldr":"How the immune system sees cancer, and how cancer learns to hide. Tumours display fragments of their proteins on MHC molecules; T cells kill the ones they recognise; the survivors are the ones that stopped showing fragments or switched on brakes."},{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/","tldr":"Cancer cells rewire how they eat. They burn glucose inefficiently but fast (the Warburg effect), gorge on glutamine and fats, and build the nucleotides and lipids needed to divide. This is why the FDG PET scan works, and why metabolism is a drug target."},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/","tldr":"Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal."},{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/","tldr":"Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit."},{"id":"telomere-maintenance","kind":"pathway","name":"Telomere maintenance & replicative immortality","route":"/pathways/telomere-maintenance/","tldr":"Normal cells can divide only a limited number of times because the protective caps on their chromosomes, telomeres, wear down. About 90% of cancers switch the cap-rebuilding enzyme telomerase back on, often through TERT promoter mutations, and roughly 10% use an alternative lengthening route (ALT), so they divide indefinitely; imetelstat is the first approved telomerase inhibitor."},{"id":"autophagy","kind":"pathway","name":"Autophagy","route":"/pathways/autophagy/","tldr":"Autophagy is the cell's recycling programme. Cancer cells, especially pancreatic and RAS-driven tumours, use it to survive starvation and drug stress, which is why hydroxychloroquine, an old malaria drug that blocks it, keeps appearing in trials."},{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","route":"/pathways/ferroptosis-cell-death/","tldr":"Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it."},{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/","tldr":"Damaged cells can stop dividing permanently instead of dying. That protects against cancer at first, but senescent cells linger, secrete inflammatory signals, and after chemotherapy can help tumours relapse, so removing them (senolytics) is a new strategy."},{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/","tldr":"Some cancer cells behave like stem cells: they can regrow the whole tumour, resist treatment, and switch identities. This plasticity explains why tumours come back and why some lung and prostate cancers transform into a different cancer type under therapy."},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/","tldr":"A tumour is a population that evolves by natural selection. Treatment kills the sensitive cells and selects the rest, which is why resistance is the rule; measuring the surviving population (MRD) and adapting therapy is the counter-strategy."},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/","tldr":"Chronic inflammation is soil for cancer: it feeds growth signals, DNA damage, and immune suppression. The NF-κB switch inside cells is the master relay, and colitis, hepatitis, and H. pylori gastritis are the clinical proof."},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/","tldr":"A developmental pathway that shapes embryos and is switched back on in basal cell skin cancer and some brain tumours. Blocking it cures most advanced basal cell carcinomas, but tumours learn to reactivate it downstream."},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/","tldr":"A cell-to-cell contact signal that decides cell fate. It drives T-cell leukaemia when mutated on, acts as a tumour suppressor in some squamous cancers when lost, and its ligand DLL3 became a drug target in small-cell lung cancer."},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/","tldr":"The relay that turns cytokine signals into gene changes. Overactive in blood cancers (JAK2 in myelofibrosis), it is also the wire that carries interferon's cancer-killing message, so tumours cut it to escape immunotherapy."},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/","tldr":"A signal that stops normal cells from dividing but, once a cancer is established, switches sides: it builds scar-like stroma, walls out immune cells, and pushes cells into a migratory state."},{"id":"hippo-yap","kind":"pathway","name":"Hippo-YAP/TAZ","route":"/pathways/hippo-yap/","tldr":"The pathway that tells organs when to stop growing. Cancers disable it so YAP and TAZ stay in the nucleus driving growth; in mesothelioma, NF2 loss does exactly that, and the first drugs against the YAP-TEAD switch are in trials."},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/","tldr":"MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s."},{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/","tldr":"KEAP1-NRF2 is the cell's antioxidant defence switch. Lung cancers often break the off-switch (KEAP1), leaving NRF2 permanently on, which detoxifies chemotherapy and radiation and makes these tumours resistant to almost everything."},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/","tldr":"A machine that opens and closes DNA so genes can be read. One in five cancers has a broken part (ARID1A, SMARCA4, PBRM1), and losing one part often creates a dependence on its twin, which is the basis for new synthetic-lethal drugs."},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/","tldr":"Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs."},{"id":"rna-splicing","kind":"pathway","name":"RNA splicing","route":"/pathways/rna-splicing/","tldr":"Genes are cut and pasted into messages before they are used. Blood cancers often carry mutations in the splicing machinery, and the errors create abnormal proteins that could serve as targets or immune flags."},{"id":"mrna-translation-eif4f","kind":"pathway","name":"mRNA translation (eIF4F / mTOR)","route":"/pathways/mrna-translation-eif4f/","tldr":"Cancer cells must make protein at furious speed. The eIF4F complex that starts protein synthesis is the funnel where growth signals converge, and drugs that pinch the funnel starve the tumour of the proteins it needs most."},{"id":"circadian-control","kind":"pathway","name":"Circadian control","route":"/pathways/circadian-control/","tldr":"Cells run on a 24-hour clock that gates cell division, DNA repair, and drug metabolism. Cancers often break their clocks, and the time of day a drug or immunotherapy is given can change how well it works."},{"id":"microbiome-tumour","kind":"pathway","name":"Microbiome-tumour interactions","route":"/pathways/microbiome-tumour/","tldr":"The bacteria in the gut, and even inside tumours, influence whether cancer starts and whether immunotherapy works. Transplanting stool from responders has made some non-responders respond."},{"id":"cancer-neuroscience","kind":"pathway","name":"Cancer neuroscience (nerve-tumour signalling)","route":"/pathways/cancer-neuroscience/","tldr":"Cancer neuroscience is the study of how tumours talk to nerves. Nerves grow into tumours and feed them signals; brain tumours even wire themselves into neural circuits. Cutting the conversation with common drugs such as beta-blockers is now being tested."},{"id":"cachexia-biology","kind":"pathway","name":"Cancer cachexia","route":"/pathways/cachexia-biology/","tldr":"The wasting syndrome that kills up to a third of cancer patients: tumours send hormonal signals (GDF-15, IL-6) that switch off appetite and burn muscle and fat. The first drug to reverse it, ponsegromab, showed weight gain in 2024."},{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/","tldr":"As we age, blood stem cells with cancer-like mutations quietly expand in most people. These clones raise leukaemia and heart disease risk, are accelerated by chemotherapy, and confuse blood tests for cancer DNA."},{"id":"field-cancerisation","kind":"pathway","name":"Field cancerisation","route":"/pathways/field-cancerisation/","tldr":"Cancer often arises from a whole region of tissue that already carries mutations, not from one rogue cell. Sun-exposed skin, smokers' airways, and Barrett's oesophagus are patchworks of mutant clones competing long before a tumour appears."},{"id":"tumor-dormancy","kind":"pathway","name":"Tumour dormancy","route":"/pathways/tumor-dormancy/","tldr":"Cancer cells can hide in bone marrow, lung, or brain for years or decades, asleep and invisible to scans and chemotherapy, then wake up. Late relapse in breast and prostate cancer is dormancy ending."},{"id":"idea-dtc-colonisation-determinants","kind":"idea","name":"What decides which disseminated cells ever colonise?","route":"/ideas/idea-dtc-colonisation-determinants/","tldr":"Most cancer cells that spread die or sleep forever; a few grow into lethal metastases. Nobody can yet tell them apart, and doing so would show whom to treat after surgery."},{"id":"idea-immune-exclusion-drivers","kind":"idea","name":"What actually holds T cells at the tumour border?","route":"/ideas/idea-immune-exclusion-drivers/","tldr":"In immune-excluded tumours T cells reach the border but cannot get in, held back by fibroblasts, matrix, abnormal vessels, CXCL12 gradients or myeloid cells, and TGF-β drugs on their own have failed. If single-cell and spatial profiling can show which stromal programme dominates in each tumour, matching the drug (TGF-β, FAP, CXCR4 or VEGF) to it could let immunotherapy work."},{"id":"idea-drugging-myc","kind":"idea","name":"Can MYC be drugged directly, and will patients tolerate it?","route":"/ideas/idea-drugging-myc/","tldr":"MYC drives half of all cancers but has no pocket for a drug and is needed by normal cells too. The first direct MYC blockers are in trials; the question is whether there is a therapeutic window."},{"id":"idea-targeting-aneuploidy","kind":"idea","name":"Is aneuploidy itself a druggable vulnerability?","route":"/ideas/idea-targeting-aneuploidy/","tldr":"Most cancers have the wrong number of chromosomes; normal cells do not. If that difference creates a specific weakness, a drug against it would spare normal tissue by definition."},{"id":"idea-neoantigen-immunogenicity-rules","kind":"idea","name":"What makes a neoantigen actually immunogenic?","route":"/ideas/idea-neoantigen-immunogenicity-rules/","tldr":"Vaccines can now encode dozens of a tumour's mutations, but only a minority provoke useful T cells. Learning the rules would make vaccines smaller, cheaper, and stronger."},{"id":"idea-dormancy-maintenance-therapy","kind":"idea","name":"Keep them asleep: dormancy maintenance as adjuvant therapy","route":"/ideas/idea-dormancy-maintenance-therapy/","tldr":"Instead of trying to kill every hidden cancer cell after surgery, keep them dormant for life with low-toxicity drugs, the way extended hormone therapy already does in breast cancer."},{"id":"idea-metabolic-vulnerability-mapping","kind":"idea","name":"Map metabolic dependencies in the patient, not the dish","route":"/ideas/idea-metabolic-vulnerability-mapping/","tldr":"Metabolic drugs keep failing because tumours switch fuels. Measuring what a patient's tumour actually eats, with tracers and PET, could pick the right metabolic drug for the right tumour."},{"id":"idea-senolytics-after-chemo","kind":"idea","name":"One-two punch: clear senescent cells after chemotherapy","route":"/ideas/idea-senolytics-after-chemo/","tldr":"Chemotherapy leaves behind senescent cells that inflame tissues and help tumours relapse. A short course of senolytic drugs afterwards might reduce relapse and long-term side effects at once."},{"id":"idea-microbiome-io-fmt","kind":"idea","name":"Microbiome transplant as a routine immunotherapy adjunct","route":"/ideas/idea-microbiome-io-fmt/","tldr":"Stool transplants from immunotherapy responders have rescued some non-responders in melanoma. If defined bacterial cocktails work as well, every immunotherapy patient could get one."},{"id":"idea-nerve-tumour-blockade","kind":"idea","name":"Cut the nerve supply to tumours with old drugs","route":"/ideas/idea-nerve-tumour-blockade/","tldr":"Nerves feed pancreatic, prostate, and other tumours. Beta-blockers and botulinum toxin are cheap, safe, and already in trials to see if severing that link slows cancer."},{"id":"idea-cachexia-gdf15-prevention","kind":"idea","name":"Treat cachexia before it starts","route":"/ideas/idea-cachexia-gdf15-prevention/","tldr":"Cachexia, the muscle wasting driven partly by the hormone GDF-15, kills cancer patients and stops chemotherapy being completed, and late muscle loss is largely irreversible. Ponsegromab, an anti-GDF-15 antibody, reversed weight loss in established cachexia in 2024; the next test is a phase 3 giving it from first-line chemotherapy in pancreatic cancer to prevent wasting rather than treat it."},{"id":"idea-chip-risk-modifiers","kind":"idea","name":"Which patients' blood clones will become leukaemia after treatment?","route":"/ideas/idea-chip-risk-modifiers/","tldr":"PARP inhibitors, platinum, and radioligand drugs can push pre-existing blood-cell clones toward leukaemia in a few patients. Predicting who could let us choose therapies more safely."},{"id":"idea-field-interception","kind":"idea","name":"Intercept cancer at the field stage","route":"/ideas/idea-field-interception/","tldr":"Whole regions of tissue carry cancer mutations long before a tumour exists. Detecting and treating the field, not the tumour, could prevent cancers rather than cure them."},{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","route":"/ideas/idea-ferroptosis-persisters/","tldr":"The cells that survive targeted therapy change shape and become unusually dependent on an antioxidant enzyme, GPX4. Hitting them in that window might stop resistance before it evolves."},{"id":"idea-splice-neoantigens","kind":"idea","name":"Shared splice-derived neoantigens as off-the-shelf vaccine targets","route":"/ideas/idea-splice-neoantigens/","tldr":"Mutations in the RNA splicing genes SF3B1, SRSF2 and U2AF1 produce the same mis-spliced proteins in patient after patient with MDS, CLL or uveal melanoma. If fragments of those proteins are displayed on common HLA molecules and seen by T cells, one off-the-shelf vaccine or TCR-T therapy could serve every SF3B1-mutant patient instead of being built per person."},{"id":"idea-chronotherapy-immunotherapy","kind":"idea","name":"Give immunotherapy in the morning","route":"/ideas/idea-chronotherapy-immunotherapy/","tldr":"Several studies found patients infused with checkpoint inhibitors earlier in the day lived longer. If a randomised trial confirms it, it is a free improvement available everywhere tomorrow."},{"id":"idea-ecdna-targeting","kind":"idea","name":"Attack extrachromosomal DNA, the engine of oncogene amplification","route":"/ideas/idea-ecdna-targeting/","tldr":"Aggressive glioblastomas, sarcomas and gastric cancers keep amplified cancer genes such as EGFR, MYC, MDM2 and CDK4 on free-floating DNA circles (ecDNA) whose copy number rises and falls quickly, letting the tumour dial resistance up and down. Cells carrying ecDNA depend on CHK1, giving a first drug target."},{"id":"basement-membrane-tissue-barriers","kind":"pathway","name":"Basement membrane & tissue barriers","route":"/pathways/basement-membrane-tissue-barriers/","tldr":"Every organ keeps its lining cells behind a thin, dense sheet of protein called the basement membrane. A tumour that has not crossed it is 'in situ' and essentially curable; crossing it is the moment cancer becomes invasive."},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/","tldr":"Seven steps the immune system must complete to kill a tumour: release of antigens, pick-up by dendritic cells, priming of T cells in lymph nodes, travel, entry into the tumour, recognition, and killing. Every immunotherapy pushes on one step; every escape blocks one."},{"id":"extrinsic-apoptosis-death-receptors","kind":"pathway","name":"Extrinsic apoptosis (death receptors)","route":"/pathways/extrinsic-apoptosis-death-receptors/","tldr":"Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers."},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/","tldr":"p53 is the cell's emergency coordinator: DNA damage, oncogene stress or lack of oxygen switch it on, and it then pauses division, orders repairs, or triggers suicide or permanent retirement, while MDM2 keeps it off in healthy cells. About half of cancers mutate p53 outright, and sarcomas, gliomas, melanomas and retinoblastomas silence it instead by amplifying MDM2 or MDM4."},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/","tldr":"Every cause of DNA damage leaves its own fingerprint in the genome: sunlight, tobacco, a faulty repair enzyme, a gut bacterium. Reading these fingerprints tells you what caused a cancer and which repair crews it is missing, which in turn predicts which drugs will work."},{"id":"oncogene-activation-two-hit","kind":"pathway","name":"Drivers, passengers & the two-hit model","route":"/pathways/oncogene-activation-two-hit/","tldr":"Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride."},{"id":"oncogenic-viruses","kind":"pathway","name":"Oncogenic viruses","route":"/pathways/oncogenic-viruses/","tldr":"About one cancer in eight worldwide is caused by a virus. HPV, hepatitis B and C, Epstein-Barr, HTLV-1, KSHV and Merkel cell polyomavirus each hijack the same brakes cancer normally has to mutate, which is why vaccines against HPV and HBV are among the most effective anti-cancer drugs ever made."},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/","tldr":"Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it."},{"id":"dna-replication-licensing","kind":"pathway","name":"DNA replication & origin licensing","route":"/pathways/dna-replication-licensing/","tldr":"Before a cell divides it must copy three billion letters of DNA exactly once, 'licensing' thousands of start points in advance and firing them in waves. Cancers driven by MYC, cyclin E or RAS fire excess start points too fast, and antimetabolites such as 5-FU, topoisomerase poisons such as irinotecan and platinum drugs all jam this copying machinery."},{"id":"mitotic-spindle-checkpoint","kind":"pathway","name":"Mitosis & the spindle assembly checkpoint","route":"/pathways/mitotic-spindle-checkpoint/","tldr":"When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies."},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/","tldr":"Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here."},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/","tldr":"Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable."},{"id":"ubiquitin-proteasome-system","kind":"pathway","name":"Ubiquitin-proteasome system & protein homeostasis","route":"/pathways/ubiquitin-proteasome-system/","tldr":"Cells tag unwanted proteins with a small marker called ubiquitin and feed them into a shredder, the proteasome. Myeloma cells, which make antibody in bulk, die if the shredder jams; and the newest drugs hijack the tagging machinery to make a cancer destroy its own oncoproteins."},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/","tldr":"A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell."},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/","tldr":"After DNA is copied, a proofreading crew fixes the letters the polymerase got wrong. Lose it and the genome fills with thousands of small errors, especially in repetitive stretches (microsatellites). Those errors make abnormal proteins that the immune system can see, which is why immunotherapy works so well in these cancers."},{"id":"base-excision-repair-parp","kind":"pathway","name":"Base excision repair, PARP & alkylation damage","route":"/pathways/base-excision-repair-parp/","tldr":"Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA."},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/","tldr":"Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials."},{"id":"glutamine-metabolism","kind":"pathway","name":"Glutamine addiction","route":"/pathways/glutamine-metabolism/","tldr":"After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door."},{"id":"lipid-metabolism-cancer","kind":"pathway","name":"Lipid synthesis, uptake & cholesterol","route":"/pathways/lipid-metabolism-cancer/","tldr":"Dividing cells need membranes, and membranes are fat. Cancers switch on the fat-building enzymes most adult tissues keep off, and in fatty environments (breast, omentum, bone marrow) they also steal lipids from neighbouring fat cells. This links obesity to cancer and offers new drug targets."},{"id":"angiogenic-switch","kind":"pathway","name":"The angiogenic switch & tumour vessels","route":"/pathways/angiogenic-switch/","tldr":"A tumour cannot grow beyond a couple of millimetres without its own blood supply. The 'switch' flips when the signals calling for new vessels (VEGF, FGF, angiopoietin) outweigh the ones holding them back (thrombospondin). The vessels that result are leaky and chaotic, which starves the tumour of oxygen, blocks drugs, and gives cancer cells a way out."},{"id":"nutrient-competition-tme","kind":"pathway","name":"Nutrient competition & metabolic immunosuppression","route":"/pathways/nutrient-competition-tme/","tldr":"Tumours and immune cells eat from the same plate. Cancer cells hoard glucose and glutamine, dump lactate and acid, and burn tryptophan and arginine into by-products that paralyse T cells. The tumour wins the food fight, and the immune system loses before it has fired a shot."},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/","tldr":"T cells that see their target for weeks on end without winning gradually shut down: they raise a set of brakes (PD-1, LAG-3, TIM-3, TIGIT), lose their ability to kill, and eventually lock this state into their DNA. Checkpoint drugs rescue the ones that are only partly exhausted; the terminally exhausted are beyond reach."},{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/","tldr":"Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy."},{"id":"myeloid-suppression-axis","kind":"pathway","name":"Myeloid suppression: TAMs, MDSCs & don't-eat-me signals","route":"/pathways/myeloid-suppression-axis/","tldr":"Tumours recruit the body's clean-up cells (macrophages and immature myeloid cells) and re-train them as bodyguards. They switch off T cells, build vessels, and, when a therapeutic antibody flags a cancer cell for eating, are told 'don't eat me' by CD47 on its surface."},{"id":"complement-in-cancer","kind":"pathway","name":"Complement in cancer","route":"/pathways/complement-in-cancer/","tldr":"Complement is a cascade of blood proteins that punches holes in things marked by antibodies and calls in inflammatory cells. Therapeutic antibodies such as rituximab use it to kill cancer cells; tumours defend themselves with shields (CD46, CD55, CD59), and the cascade's own by-products (C5a) can recruit the myeloid cells that protect the tumour."},{"id":"nk-cell-recognition","kind":"pathway","name":"NK-cell recognition: missing self & stress ligands","route":"/pathways/nk-cell-recognition/","tldr":"Natural killer cells patrol for cells that have lost their identity papers (MHC-I) or that display stress flags. Cancers that hide from T cells by dropping MHC-I become visible to NK cells, unless they also shed the stress flags, wrap themselves in a second inhibitory badge (HLA-E), or soak the neighbourhood in TGF-β."},{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","route":"/pathways/invasion-ecm-degradation/","tldr":"To invade, a cancer cell must grip the scaffolding around it, dissolve a path with enzymes, and pull itself forward, alone or in a chain led by a scout cell. Fibroblasts often cut the trail first. The enzyme blockers of the 1990s failed; today's targets are the grip (integrins, FAK) and the trail-makers."},{"id":"intravasation-ctc-survival","kind":"pathway","name":"Intravasation & circulating tumour cells","route":"/pathways/intravasation-ctc-survival/","tldr":"Getting into the bloodstream and surviving there is brutal: cells are ripped from their neighbours, battered by flow, and hunted by NK cells. Fewer than one in a thousand survive. The ones that do travel in clusters, wear a cloak of platelets, or ride with neutrophils. Liquid biopsies catch what is left."},{"id":"pre-metastatic-niche","kind":"pathway","name":"The pre-metastatic niche","route":"/pathways/pre-metastatic-niche/","tldr":"Before a single cancer cell arrives, the primary tumour sends parcels ahead: tiny vesicles (exosomes) and hormones that recruit bone-marrow cells to a distant organ and remodel it into fertile soil. By the time the seed lands, the bed is already made."},{"id":"organ-tropism-seed-soil","kind":"pathway","name":"Organ tropism: seed and soil","route":"/pathways/organ-tropism-seed-soil/","tldr":"Breast cancer goes to bone, lung, liver and brain; prostate cancer to bone; colon cancer to liver; uveal melanoma almost only to liver. Paget's 1889 idea still holds: where a cancer spreads depends on both the seed (the cell's programme) and the soil (the organ's welcome). Each soil has its own vicious cycle, and some are druggable."},{"id":"blood-brain-barrier-metastasis","kind":"pathway","name":"The blood-brain barrier & brain metastasis","route":"/pathways/blood-brain-barrier-metastasis/","tldr":"The brain's blood vessels are sealed tight and fitted with pumps that eject most drugs. That protects the brain from poisons but also from chemotherapy and antibodies. Cancer cells that do squeeze through recruit the brain's own support cells, astrocytes, to feed and shield them."},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/","tldr":"Tumours recruit the body's repair cells, fibroblasts, and keep them in wound-healing mode forever. The scar tissue they lay down (desmoplasia) squeezes blood vessels shut, walls out immune cells, stiffens the tissue in a way that itself tells cancer cells to grow, and is why pancreatic cancer is so hard to treat."},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/","tldr":"When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug."},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/","tldr":"Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses."},{"id":"drug-efflux-pumps","kind":"pathway","name":"Drug efflux pumps (ABC transporters)","route":"/pathways/drug-efflux-pumps/","tldr":"Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip."},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/","tldr":"Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine."},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/","tldr":"Scientists have given more than a dozen answers to what cancer is: mutated genes, runaway evolution, misbehaving stem cells, disordered tissue, ancient cell programmes, broken chromosomes, metabolism, epigenetic switches, unhealed wounds, a failed immune system, ageing tissue, force or electricity. This map shows each theory, who proposed it, what held up, and how the ideas connect."}]}