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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Spatial heterogeneity of FAP expression and radioligand uptake was assessed in human pancreatic ductal adenocarcinoma (PDAC) tissues using immunofluorescence and autoradiography with [\n                      <jats:sup>1<\/jats:sup>\n                      \u2076\n                      <jats:sup>1<\/jats:sup>\n                      \u00a0Tb]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 (\u03b3H2AX), clonogenic survival, spheroid growth, and cytokine profiling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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, [\n                      <jats:sup>1<\/jats:sup>\n                      \u2076\n                      <jats:sup>1<\/jats:sup>\n                      \u00a0Tb]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\u2013CAF 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 (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), associated with increased IL-6 and TGF-\u03b2 secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-026-08099-4","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:26:58Z","timestamp":1785306418000},"page":"7313-7326","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Context-dependent efficacy of fibroblast activation protein-targeted radionuclide therapy (FAP-TRT): the dual role of CAFs"],"prefix":"10.1007","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2377-2639","authenticated-orcid":false,"given":"Chunhui","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Kurniawan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihe","family":"Ming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten W.","family":"Nijkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evert","family":"van den Broek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Noordzij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andor W. 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