CAF Subtypes (myCAF / iCAF / apCAF)

Because cancer-associated fibroblasts carry no defining genetic alteration, they are classified by morphological, molecular and spatial features, largely from single-cell RNA sequencing. Across many solid tumors these classifications converge on two main subtypes with similar gene signatures: the myofibroblastic CAF (myCAF), characterized by collagen and extracellular matrix gene expression and recalling the features of myofibroblasts, and the inflammatory CAF (iCAF), enriched for cytokine and chemokine genes such as IL-6, CXCL12, CXCL1, IL-1alpha and LIF. A third subtype, the antigen-presenting CAF (apCAF), expresses MHC class II genes, derives from mesothelial cells, and has so far been described only in some organs, including pancreatic, lung and breast cancer and cholangiocarcinoma.

The two main subtypes are generated by distinct paracrine axes, TGF-beta driving myCAF and IL-1alpha driving iCAF differentiation. Position matters as well: in co-culture of pancreatic stellate cells with cancer organoids, cells in direct contact with cancer cells acquire myCAF morphology and genes, whereas cells kept out of contact become iCAFs, and the states can interconvert according to trophic and spatial cues.

Classification remains contested. Terminology differs between studies, some tumor types yield additional subtypes, and the markers used to separate iCAFs from myCAFs are not strictly specific - there are matrix-producing CAFs with low alpha-SMA, and alpha-SMA-high CAFs with immunosuppressive features. A functional classification based on activation of whole pathways, rather than single marker genes, has been proposed as the way forward.