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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.
Resident fibroblasts, pancreatic and hepatic stellate cells, and mesenchymal stromal cells are activated by TGF-β, PDGF, IL-1, Hedgehog ligand from tumour cells and by stiffness itself (YAP/TAZ feed-forward) into myofibroblastic CAFs (myCAF: αSMA, collagen I/III, FAP, LRRC15), inflammatory CAFs (iCAF: IL-6, LIF, CXCL12, driven by IL-1/JAK-STAT) and antigen-presenting CAFs. They deposit and crosslink collagen (LOX/LOXL2), hyaluronan and fibronectin, raising interstitial pressure (collapsing vessels, blocking drug delivery) and stiffness, which signals through integrins → FAK → RHO → YAP/TAZ to drive proliferation, EMT and chemoresistance in tumour cells; aligned fibres guide invasion; TGF-β-CAFs exclude T cells. CAFs also feed tumours (alanine, lipids, exosomes) and shield them. Depleting all fibroblasts (Shh-deleted or αSMA-ablated mice) made tumours more aggressive, and the SMO inhibitor vismodegib and hyaluronidase PEGPH20 failed in PDAC: hence a shift to reprogramming (vitamin D receptor agonists, losartan/angiotensin blockade in trials, IL-1/JAK for iCAF, LRRC15 or FAP targeting with radioligands and CAR-T) and to exploiting FAP for imaging (FAPI PET) and therapy.
Builders hired to repair a wall who never stop: they pour concrete around the tumour until the roads are blocked (vessels), the police cannot get in (T cells), and the very hardness of the concrete tells the tenants to multiply. Demolishing the builders' work made things worse; the newer plan is to retrain them.
It explains why one biopsy can mislead and why chemotherapy selects for the protective neighbourhood, an argument for spatial rather than bulk profiling.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The definitive negative result for first-generation stromal targeting: a biomarker-selected population, a drug that did what it was designed to do to the matrix, and no survival benefit; the stroma ideas on this page start from here.
The reference for why pancreatic microenvironment trials read as a list of failures and what the field now means by remodelling rather than removing the stroma.
Fibroblasts are part of the immune conversation, not just a physical barrier, which is why stromal and immune strategies are now designed together.
It made subtyping possible on the archived tissue every hospital has, and it retired one of the four Bailey subtypes.
The myCAF and iCAF distinction is why 'target the stroma' became 'target a fibroblast state', and IL-6 blockade combinations follow from it.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares The tumour microenvironment in pancreatic cancer: clinical challenges and opportunities, Immune exclusion, JAK-STAT signalling, Microenvironment and inflammation: tumours as wounds that do not heal and the tags mechanism, mechanics-atlas.
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Shares PD-1, Pancreatic ductal adenocarcinoma, Colorectal cancer and the tags mechanism, mechanics-atlas.