{"entity":{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","aka":[],"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.","summary":"TGF-β binds TGFBR2/TGFBR1 (ALK5) to phosphorylate SMAD2/3, which with SMAD4 regulates transcription. Early tumour suppressor (cytostatic; SMAD4 and TGFBR2 loss in pancreatic and MSI colorectal cancer) and later promoter of EMT, CAF activation, immune exclusion (T-cell exclusion in bladder and CRC), and metastasis. Bintrafusp alfa (PD-L1/TGF-β trap) failed in phase 3 (NSCLC, biliary); galunisertib was discontinued; SRK-181 (latent TGF-β1) and dalutrafusp continue. Blocking TGF-β to re-sensitise cold tumours remains an active, unproven idea.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/TGF_beta_signaling_pathway","links":[{"label":"Tauriello et al., TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis (Nature 2018)","url":"https://doi.org/10.1038/nature25492"}],"tags":["mechanism"],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":[],"targets":["acvr1"],"drugs":[],"companies":[],"institutions":["mskcc","vall-dhebron","cold-spring-harbor"],"pathways":["emt","tumor-microenvironment","metastatic-cascade","pd1-checkpoint"],"terms":["immune-exclusion","cold-vs-hot","desmoplasia"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Massagué (MSK, TGF-β biology and metastasis); Tauriello & Batlle (IRB Barcelona, TGF-β and immune exclusion in CRC); Sheppard (UCSF, integrin activation)."],"analogy":"A town planner who first refuses all new building (tumour suppressor) and then, corrupted, builds walls and moats around the tumour that keep the police out (immune exclusion).","nodes":[{"id":"lig","label":"Latent TGF-β (activated by integrins)","x":12,"y":40},{"id":"rec","label":"TGFBR2 / ALK5","x":35,"y":40},{"id":"smad","label":"SMAD2/3-SMAD4","x":58,"y":40},{"id":"cyto","label":"Cytostasis (early)","x":80,"y":15},{"id":"emt","label":"EMT, CAF activation","x":80,"y":45},{"id":"excl","label":"T-cell exclusion","x":80,"y":75},{"id":"smad4","label":"SMAD4 loss (PDAC)","x":35,"y":80}],"edges":[{"from":"lig","to":"rec","type":"activates"},{"from":"rec","to":"smad","type":"activates"},{"from":"smad","to":"cyto","type":"activates"},{"from":"smad","to":"emt","type":"activates"},{"from":"smad","to":"excl","type":"activates"},{"from":"smad4","to":"smad","type":"inhibits"}],"interventions":["TGF-β traps and antibodies (mostly failed: bintrafusp alfa); latent-TGF-β1-selective agents in trials","ALK5 inhibitors (vactosertib) with IO in trials","Integrin αvβ6/αvβ8 blockade to prevent activation (investigational)"]},"route":"/pathways/tgf-beta/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"target":[{"id":"acvr1","kind":"target","name":"ACVR1 (ALK2)","route":"/targets/acvr1/"},{"id":"acvr2a","kind":"target","name":"ACVR2A","route":"/targets/acvr2a/"},{"id":"il10","kind":"target","name":"Interleukin-10 (IL10)","route":"/targets/il10/"},{"id":"smad2","kind":"target","name":"SMAD2","route":"/targets/smad2/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tgfb1","kind":"target","name":"TGFB1","route":"/targets/tgfb1/"},{"id":"tgfbr1","kind":"target","name":"TGFBR1","route":"/targets/tgfbr1/"},{"id":"tgfbr2","kind":"target","name":"TGFBR2","route":"/targets/tgfbr2/"}],"institution":[{"id":"cold-spring-harbor","kind":"institution","name":"Cold Spring Harbor Laboratory","route":"/institutions/cold-spring-harbor/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"vall-dhebron","kind":"institution","name":"Vall d'Hebron University Hospital / VHIO","route":"/institutions/vall-dhebron/"}],"pathway":[{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"gastric-cancer-signalling","kind":"pathway","name":"Gastric cancer (KEGG map)","route":"/pathways/gastric-cancer-signalling/"},{"id":"hepatocellular-carcinoma-signalling","kind":"pathway","name":"Hepatocellular carcinoma (KEGG map)","route":"/pathways/hepatocellular-carcinoma-signalling/"},{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","route":"/pathways/invasion-ecm-degradation/"},{"id":"nk-cell-recognition","kind":"pathway","name":"NK-cell recognition: missing self & stress ligands","route":"/pathways/nk-cell-recognition/"},{"id":"organ-tropism-seed-soil","kind":"pathway","name":"Organ tropism: seed and soil","route":"/pathways/organ-tropism-seed-soil/"},{"id":"pancreatic-cancer-signalling","kind":"pathway","name":"Pancreatic cancer (KEGG map)","route":"/pathways/pancreatic-cancer-signalling/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"metastatic-cascade","kind":"pathway","name":"The metastatic cascade","route":"/pathways/metastatic-cascade/"},{"id":"tumor-dormancy","kind":"pathway","name":"Tumour dormancy","route":"/pathways/tumor-dormancy/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"}],"term":[{"id":"cancer-associated-fibroblasts","kind":"term","name":"Cancer-associated fibroblasts (CAFs)","route":"/terms/cancer-associated-fibroblasts/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"},{"id":"activating-invasion-metastasis","kind":"term","name":"Hallmark: activating invasion and metastasis","route":"/terms/activating-invasion-metastasis/"},{"id":"avoiding-immune-destruction","kind":"term","name":"Hallmark: avoiding immune destruction","route":"/terms/avoiding-immune-destruction/"},{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"}],"paper":[{"id":"paper-commands-luspatercept-mds-lancet-2023","kind":"paper","name":"COMMANDS: luspatercept versus epoetin alfa as first treatment for anaemia in lower-risk MDS needing transfusions","route":"/key-papers/paper-commands-luspatercept-mds-lancet-2023/"},{"id":"paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009","kind":"paper","name":"DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer","route":"/key-papers/paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009/"},{"id":"paper-bailey-molecular-subtypes-pancreatic-nature-2016","kind":"paper","name":"Genomic analyses identify molecular subtypes of pancreatic cancer","route":"/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/"},{"id":"paper-noe-cyst-malignant-progression-genomics-nat-commun-2020","kind":"paper","name":"Genomic characterization of malignant progression in neoplastic pancreatic cysts","route":"/key-papers/paper-noe-cyst-malignant-progression-genomics-nat-commun-2020/"},{"id":"paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995","kind":"paper","name":"Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability","route":"/key-papers/paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995/"},{"id":"paper-kalluri-weinberg-emt-basics-jci-2009","kind":"paper","name":"Kalluri and Weinberg 2009: the basics of epithelial-mesenchymal transition","route":"/key-papers/paper-kalluri-weinberg-emt-basics-jci-2009/"},{"id":"paper-lamouille-emt-molecular-mechanisms-nrmcb-2014","kind":"paper","name":"Lamouille 2014: molecular mechanisms of epithelial-mesenchymal transition","route":"/key-papers/paper-lamouille-emt-molecular-mechanisms-nrmcb-2014/"},{"id":"paper-mani-emt-stem-cell-properties-cell-2008","kind":"paper","name":"Mani 2008: the epithelial-mesenchymal transition generates cells with properties of stem cells","route":"/key-papers/paper-mani-emt-stem-cell-properties-cell-2008/"},{"id":"paper-biankin-pancreatic-exomes-axon-guidance-nature-2012","kind":"paper","name":"Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes","route":"/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/"},{"id":"paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015","kind":"paper","name":"Stromal gene expression defines poor-prognosis subtypes in colorectal cancer","route":"/key-papers/paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015/"},{"id":"paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","kind":"paper","name":"TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","route":"/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/"},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/"}],"idea":[{"id":"idea-pdac-stromal-reprogramming-not-depletion","kind":"idea","name":"Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint","route":"/ideas/idea-pdac-stromal-reprogramming-not-depletion/"},{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/"},{"id":"idea-immune-exclusion-drivers","kind":"idea","name":"What actually holds T cells at the tumour border?","route":"/ideas/idea-immune-exclusion-drivers/"}],"company":[{"id":"isarna-therapeutics","kind":"company","name":"Isarna Therapeutics","route":"/companies/isarna-therapeutics/"}]}}