Cancer-associated fibroblast reprogramming (CAF reprogramming)

Cancer-associated fibroblast (CAF) reprogramming is a therapeutic strategy aimed at converting pro-tumorigenic CAFs into quiescent or tumor-restraining phenotypes. Unlike CAF depletion, which can paradoxically accelerate tumor progression by removing protective stromal elements, reprogramming seeks to modulate the functional state of these cells to normalize the tumor microenvironment [1, 5]. CAFs are a dominant cell type in many solid tumors, where they drive growth, metastasis, and therapy resistance by remodeling the extracellular matrix (ECM) and secreting immunosuppressive factors [2, 11]. Key molecular targets for this approach include the Vitamin D receptor (VDR), which when activated by ligands like calcipotriol, induces a quiescent state in pancreatic stellate cells [2, 5]. Other strategies involve inhibiting transforming growth factor-beta (TGF-β), interleukin-1 (IL-1), or Janus kinase (JAK) signaling to suppress the myofibroblastic and inflammatory phenotypes of CAFs [2, 10]. By successfully reprogramming the stroma, clinicians aim to reduce interstitial fluid pressure, enhance the delivery of chemotherapy, and restore the efficacy of immune checkpoint inhibitors [1, 9].

Other names

CAF normalizationCAF deactivationStromal reprogrammingPhenotypic switching of CAFsCancer-associated fibroblast phenotypic conversion

Agonism of the Vitamin D receptor or Retinoic Acid receptor to induce fibroblast quiescence; antagonism of TGF-beta, IL-1, or JAK/STAT pathways to inhibit the transition of fibroblasts into activated, pro-tumorigenic myofibroblastic or inflammatory phenotypes [1, 2, 5].