Fibroblast activation, desmoplasia & matrix stiffness

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.