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Fibroblast Activation Protein Inhibitor–Based Radionuclide Therapies: Current Status and Future Directions

Manish Ora, Neetu Soni, Aftab Hasan Nazar, Manish Dixit, Rohit Singh, Savita Puri, Michael M. Graham and Sanjay Gambhir
Journal of Nuclear Medicine June 2023, jnumed.123.265594; DOI: https://doi.org/10.2967/jnumed.123.265594

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  • FIGURE 1.
    FIGURE 1.

    Activating pathways, sources, and important functions of CAFs in TME. CAFs may arise from quiescent fibroblasts by physiologic stresses and inflammatory signals, including TGF-β, platelet-derived growth factor, fibroblast growth factor 2, interleukins, and tumor-necrosis factor. Proinflammatory conditions (TGF-β and reactive oxygen species) cause deficiency in base excision repair. This deficiency generates unrepaired DNA strand breaks and may reprogram fibroblasts into CAFs. Other differentiation pathways involve adipocytes, pericytes, and smooth muscle cells. Mesenchymal stem cells may transform into CAFs by epithelial–mesenchymal transition. This pathway involves stimulating molecules such as TGF-β, C–C chemokine ligand 2, C–C chemokine ligand 5, and C-X-C chemokine ligand 12. Endothelial and epithelial cells may also be transformed into CAFs through endothelial-to-mesenchymal transition and epithelial-to-mesenchymal transition. These activated CAFs interact with tumor and immune cells to produce prooncogenic environment. CCL = chemokine ligand; CXCL = C-X-C chemokine ligand; FGF = fibroblast growth factor; IL = interleukin; PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; TNF = tumor-necrosis factor.

  • FIGURE 2.
    FIGURE 2.

    CAF-targeting strategies for anti-CAF therapies. CAF activation and function can be suppressed by inhibiting signaling pathways leading to activation. These include TGF-β, interleukin-6, C–C chemokine ligand 2, C–C chemokine ligand 5, and C-X-C chemokine ligand 12. CAF depletion may be achieved by targeting FAP, α-smooth muscle actin, and platelet-derived growth factor receptors. Another strategy is to restrict extracellular matrix remodeling by targeting matrix proteins such as matrix metalloproteinases, hyaluronan, tenascin-C, and focal adhesion kinase. CCL = chemokine ligand; CXCL = C-X-C chemokine ligand; dsRNA = double-stranded RNA; ECM = extracellular matrix; FAK = focal adhesion kinase; IL = interleukin; MMP = matrix metalloproteinase; PDGFR = platelet-derived growth factor receptor.

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