Scholarlink

Abstract <p>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.</p> Methods <p>Spatial heterogeneity of FAP expression and radioligand uptake was assessed in human pancreatic ductal adenocarcinoma (PDAC) tissues using immunofluorescence and autoradiography with [<sup>1</sup>⁶<sup>1</sup>&#xa0;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.</p> Results <p>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, [<sup>1</sup>⁶<sup>1</sup>&#xa0;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 (<i>P</i> &lt; 0.001), associated with increased IL-6 and TGF-β secretion.</p> Conclusion <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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Context-dependent efficacy of fibroblast activation protein-targeted radionuclide therapy (FAP-TRT): the dual role of CAFs

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月29日

查看全文
  • Chunhui Wu,
  • Ahmad Kurniawan,
  • Ge Li,
  • Zihe Ming,
  • Maarten W. Nijkamp,
  • Evert van den Broek,
  • Walter Noordzij,
  • Andor W. J. M. Glaudemans,
  • Ines F. Antunes,
  • Bart Cornelissen

摘要

Abstract

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.