European journal of nuclear medicine and molecular imaging · 2026
Context-dependent efficacy of fibroblast activation protein-targeted radionuclide therapy (FAP-TRT): the dual role of CAFs.
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Wu Chunhui, Kurniawan Ahmad, Li Ge, Ming Zihe, Nijkamp Maarten W, van den Broek Evert, Noordzij Walter, Glaudemans Andor W J M, Antunes Ines F, Cornelissen Bart
Аннотация
UNLABELLED: Fibroblast activation protein-targeted radionuclide therapy (FAP-TRT) shows promise across multiple cancers, but clinical responses remain variable. Here, we aim to investigate how the presence, abundance, and spatial organisation of FAP-expressing cancer-associated fibroblasts (CAFs) relative to tumour cells influence the efficacy of FAP-TRT, to further optimisation.
METHODS: Spatial heterogeneity of FAP expression and radioligand uptake was assessed in human pancreatic ductal adenocarcinoma (PDAC) tissues using immunofluorescence and autoradiography with [1⁶1 Tb]Tb-FAPI-46. Mechanistic studies were conducted in vitro using PSN-1 tumour cells and FAP-expressing CAFs in 2D cultures and 3D spheroids, including mono- and co-culture systems with defined tumour-to-CAF ratios and spatial configurations. Cellular uptake and nuclear absorbed dose were quantified, and radiobiological effects were evaluated using DNA damage (γH2AX), clonogenic survival, spheroid growth, and cytokine profiling.
RESULTS: PDAC tissues exhibited pronounced spatial heterogeneity in FAP expression and radioligand uptake. In vitro, uptake alone did not predict absorbed dose or biological response. In 2D models, [1⁶1 Tb]Tb-FAPI-46 did not significantly reduce clonogenic survival or increase DNA damage response. In 3D spheroids, FAP-TRT induced dose-dependent DNA damage and growth inhibition. Mixed tumour-CAF spheroids showed more uniform DNA damage and stronger growth suppression than layered models. CAF-containing models attenuated tumour-cell DNA damage and growth inhibition compared to models without CAFs (P < 0.001), associated with increased IL-6 and TGF-β secretion.
CONCLUSION: FAP-expressing CAFs have a dual, context-dependent role in FAP-TRT, enhancing tumour irradiation through crossfire while also limiting tumour control potentially through radioligand partitioning towards the stromal compartment and CAF-derived paracrine signalling. These findings identify spatial organisation and CAF radiobiology as key determinants of FAP-TRT efficacy.
METHODS: Spatial heterogeneity of FAP expression and radioligand uptake was assessed in human pancreatic ductal adenocarcinoma (PDAC) tissues using immunofluorescence and autoradiography with [1⁶1 Tb]Tb-FAPI-46. Mechanistic studies were conducted in vitro using PSN-1 tumour cells and FAP-expressing CAFs in 2D cultures and 3D spheroids, including mono- and co-culture systems with defined tumour-to-CAF ratios and spatial configurations. Cellular uptake and nuclear absorbed dose were quantified, and radiobiological effects were evaluated using DNA damage (γH2AX), clonogenic survival, spheroid growth, and cytokine profiling.
RESULTS: PDAC tissues exhibited pronounced spatial heterogeneity in FAP expression and radioligand uptake. In vitro, uptake alone did not predict absorbed dose or biological response. In 2D models, [1⁶1 Tb]Tb-FAPI-46 did not significantly reduce clonogenic survival or increase DNA damage response. In 3D spheroids, FAP-TRT induced dose-dependent DNA damage and growth inhibition. Mixed tumour-CAF spheroids showed more uniform DNA damage and stronger growth suppression than layered models. CAF-containing models attenuated tumour-cell DNA damage and growth inhibition compared to models without CAFs (P < 0.001), associated with increased IL-6 and TGF-β secretion.
CONCLUSION: FAP-expressing CAFs have a dual, context-dependent role in FAP-TRT, enhancing tumour irradiation through crossfire while also limiting tumour control potentially through radioligand partitioning towards the stromal compartment and CAF-derived paracrine signalling. These findings identify spatial organisation and CAF radiobiology as key determinants of FAP-TRT efficacy.