# TGF-β signalling

Source: https://onco.cc/pathways/tgf-beta/  
OnCo record `tgf-beta` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- 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).
- 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)

## 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/TGF_beta_signaling_pathway
- Tauriello et al., TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis (Nature 2018): https://doi.org/10.1038/nature25492

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- targets: [ACVR1 (ALK2)](https://onco.cc/targets/acvr1/), [ACVR2A](https://onco.cc/targets/acvr2a/), [Interleukin-10 (IL10)](https://onco.cc/targets/il10/), [SMAD2](https://onco.cc/targets/smad2/), [SMAD4](https://onco.cc/targets/smad4/), [TGFB1](https://onco.cc/targets/tgfb1/), [TGFBR1](https://onco.cc/targets/tgfbr1/), [TGFBR2](https://onco.cc/targets/tgfbr2/)
- institutions: [Cold Spring Harbor Laboratory](https://onco.cc/institutions/cold-spring-harbor/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [Vall d'Hebron University Hospital / VHIO](https://onco.cc/institutions/vall-dhebron/)
- pathways: [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [Epithelial-mesenchymal transition & drug efflux](https://onco.cc/pathways/emt/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Gastric cancer (KEGG map)](https://onco.cc/pathways/gastric-cancer-signalling/), [Hepatocellular carcinoma (KEGG map)](https://onco.cc/pathways/hepatocellular-carcinoma-signalling/), [Invasion: proteases, adhesion & the invasive front](https://onco.cc/pathways/invasion-ecm-degradation/), [NK-cell recognition: missing self & stress ligands](https://onco.cc/pathways/nk-cell-recognition/), [Organ tropism: seed and soil](https://onco.cc/pathways/organ-tropism-seed-soil/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [The metastatic cascade](https://onco.cc/pathways/metastatic-cascade/), [Tumour dormancy](https://onco.cc/pathways/tumor-dormancy/), [Tumour microenvironment (TME)](https://onco.cc/pathways/tumor-microenvironment/)
- terms: [Cancer-associated fibroblasts (CAFs)](https://onco.cc/terms/cancer-associated-fibroblasts/), [Desmoplasia (tumour stroma)](https://onco.cc/terms/desmoplasia/), [Hallmark: activating invasion and metastasis](https://onco.cc/terms/activating-invasion-metastasis/), [Hallmark: avoiding immune destruction](https://onco.cc/terms/avoiding-immune-destruction/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune exclusion](https://onco.cc/terms/immune-exclusion/)
- key papers: [COMMANDS: luspatercept versus epoetin alfa as first treatment for anaemia in lower-risk MDS needing transfusions](https://onco.cc/key-papers/paper-commands-luspatercept-mds-lancet-2023/), [DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer](https://onco.cc/key-papers/paper-iacobuzio-donahue-dpc4-failure-pattern-autopsy-jco-2009/), [Genomic analyses identify molecular subtypes of pancreatic cancer](https://onco.cc/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/), [Genomic characterization of malignant progression in neoplastic pancreatic cysts](https://onco.cc/key-papers/paper-noe-cyst-malignant-progression-genomics-nat-commun-2020/), [Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability](https://onco.cc/key-papers/paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995/), [Kalluri and Weinberg 2009: the basics of epithelial-mesenchymal transition](https://onco.cc/key-papers/paper-kalluri-weinberg-emt-basics-jci-2009/), [Lamouille 2014: molecular mechanisms of epithelial-mesenchymal transition](https://onco.cc/key-papers/paper-lamouille-emt-molecular-mechanisms-nrmcb-2014/), [Mani 2008: the epithelial-mesenchymal transition generates cells with properties of stem cells](https://onco.cc/key-papers/paper-mani-emt-stem-cell-properties-cell-2008/), [Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes](https://onco.cc/key-papers/paper-biankin-pancreatic-exomes-axon-guidance-nature-2012/), [Stromal gene expression defines poor-prognosis subtypes in colorectal cancer](https://onco.cc/key-papers/paper-calon-stromal-gene-expression-poor-prognosis-colorectal-nat-genet-2015/), [TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis](https://onco.cc/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/), [The consensus molecular subtypes of colorectal cancer](https://onco.cc/key-papers/paper-cms-guinney-nat-med-2015/)
- ideas: [Reprogramme the stroma rather than remove it: second-generation stromal trials with a stromal biomarker and a survival endpoint](https://onco.cc/ideas/idea-pdac-stromal-reprogramming-not-depletion/), [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/), [What actually holds T cells at the tumour border?](https://onco.cc/ideas/idea-immune-exclusion-drivers/)
- companies: [Isarna Therapeutics](https://onco.cc/companies/isarna-therapeutics/)

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