# TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis

Source: https://onco.cc/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/  
OnCo record `paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Mice given all four of the main bowel cancer mutations grew tumours that spread and, like most human bowel cancers, ignored immunotherapy. Blocking TGF-beta let the immune system in, stopped the spread, and made the tumours answer checkpoint drugs.

## Summary

Mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells were crossed to analyse the interplay between genetic alterations and the tumour microenvironment. Quadruple-mutant mice developed metastatic intestinal tumours displaying key hallmarks of human microsatellite-stable colorectal cancer, including low mutational burden, T-cell exclusion and TGF-beta-activated stroma. Inhibition of the PD-1 and PD-L1 checkpoint provoked only a limited response. Inhibition of TGF-beta unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis, and in mice with progressive liver metastatic disease, blockade of TGF-beta signalling rendered tumours susceptible to anti-PD-1 and anti-PD-L1 therapy. Increased TGF-beta in the microenvironment therefore represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the T-helper-1 effector phenotype.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature
- Year: 2018
- DOI: 10.1038/nature25492
- Authors: Tauriello DVF, Palomo-Ponce S, Stork D, et al.
- Findings: Quadruple-mutant mice reproduce microsatellite-stable human disease: low mutational burden, T-cell exclusion, TGF-beta-activated stroma.; PD-1 or PD-L1 blockade alone gave only a limited response.; TGF-beta inhibition prevented metastasis and made liver metastases susceptible to checkpoint blockade.
- What it means: It is the clearest mechanistic answer to why microsatellite-stable colorectal cancer resists immunotherapy, and the rationale for every TGF-beta plus checkpoint combination now in trials in this disease.
- Caveats: Mouse genetics; no clinical trial has yet reproduced the effect in patients.; TGF-beta blockade carries cardiac and epithelial toxicity that has limited the clinical agents.

## Sources

- Tauriello et al., Nature 2018: TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis: https://doi.org/10.1038/nature25492
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29443964/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [APC](https://onco.cc/targets/apc/), [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/), [SMAD4](https://onco.cc/targets/smad4/), [TGFB1](https://onco.cc/targets/tgfb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [The metastatic cascade](https://onco.cc/pathways/metastatic-cascade/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune exclusion](https://onco.cc/terms/immune-exclusion/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/)
- journals: [Nature](https://onco.cc/journals/nature/)

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