Fig. 5

Signaling of three important CAFs in TIME of PDAC. A Tumor cells promote the activation of iCAFs through CTGF and so on. Activated iCAFs release a large number of factors that act on receptors such as LIFR, CXCR4, NGL-1, CD44, and HIP1R on tumor cells to promote proliferation, metabolism, metastasis, and stemness. iCAFs promote the proliferation and M2 polarization of TAMs by releasing a variety of factors. TAMs can promote iCAFs to release more tumor-promoting factors through OSM-OSMR. B Tumor cells upregulate SHH signaling to recruit tumor-suppressing myCAFs. Both tumor cells and myCAFs can promote the proliferation of each other by upregulating TGF-β signaling. myCAFs show tumor suppression or tumor promotion after being activated by TGF-β, which may depend on the time of tumor progression. TGF-β and CXCL12 act on the corresponding receptors on CD8⁺ T cells to mediate their exhaustion. C Tumor cells promote the transformation of mesothelial cells into apCAFs through TGF-β and IL-1, thereby inducing the proliferation of Tregs. Red arrows represent tumor-promoting processes, green arrows represent tumor-inhibiting processes, blue arrows indicate that the process of promoting or inhibiting tumor has not yet been determined. Pink circles represent possible treatment strategies. iCAF: inflammatory CAF; FAP: fibroblast activation protein; CTGF: connective tissue growth factor; LIF: leukemia inhibitory factor; NetG1: Netrin G1; SPP1: secreted phosphoprotein 1; OSM: oncostatin M; Pin1: peptidylpropyl isomerase; TAM: tumor-associated macrophage; myCAF: myofibroblastic CAF; SHH: sonic hedgehog; αSMA: α-smooth muscle actin; apCAF: antigen-presenting CAF