Explore the vast range of titles available.

Purpose The role of fibroblast activation protein (FAP)-targeted imaging in systemic vasculitis is currently unclear. We aimed to evaluate the clinical value of fluorine-18-labeled FAP inhibitor 42 ([ 18 F]FAPI-42) in patients with systemic vasculitis and to compare with [ 18 F]fluorodeoxyglucose (FDG) imaging. Methods Patients with systemic vasculitis who underwent dual-tracer PET/CT([ 18 F]FDG and [ 18 F]FAPI) imaging from September 2020 to March 2022 were retrospectively analyzed. Positive lesions are defined as vascular/extravascular lesions with increased tracer uptake above surrounding background, which cannot be attributed to the physiologic biodistribution of the radiotracer. The vascular/extravascular lesion detection rate and semiquantitative values (SUVmax, TBR blood and TBR liver ) of [ 18 F]FAPI and [ 18 F]FDG were compared, and the correlation between the extent and range of tracer uptake and levels of inflammatory markers was investigated. Results Thirty patients (13 males and 17 females; mean age, 52.5 ± 17.2 years) with systemic vasculitis were included (17 large vessel vasculitis, 10 anti-neutrophil cytoplasmic antibody-associated vasculitis, 2 Behcet’s disease and 1 polyarteritis nodosa). [ 18 F]FDG PET/CT had positive findings in 93.3% (28/30) of patients, while [ 18 F]FAPI PET/CT had positive findings in all patients (100%, P  = 0.500). Compared with [ 18 F]FDG PET/CT, [ 18 F]FAPI PET/CT detected more lesions (161/168 vs. 145/168, P  = 0.005), and more extensive vascular involvement in 60% (18/30) of patients. Although SUVmax did not differ significantly between [ 18 F]FAPI and [ 18 F]FDG (median, 5.94 vs. 5.46, P  = 0.517), [ 18 F]FAPI had higher TBR liver (median, 9.59 vs. 3.15, P  < 0.001) and TBR blood (median, 5.45 vs. 4.20, P  = 0.006). The total number of positive lesions in FAPI PET/CT show a moderate correlation with erythrocyte sedimentation rate ( r s =0.478, P  = 0.008) and C-reactive protein ( r s =0.486, P  = 0.006). After treatment, follow-up FAPI PET/CT of 6 patients showed decreased SUVmax, TBR and number of detected lesions, paralleling the clinical remission. Conclusion [ 18 F]FAPI PET/CT imaging is a promising imaging modality for the diagnosis and therapeutic monitoring of systemic vasculitis.

The therapeutic potential of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors is highly recognized, yet the complex and immunosuppressive nature of the tumor microenvironment, poor accessibility, and the instability of target antigens pose substantial challenges. Here, we present an mRNA-LNP-based therapeutic strategy that delivers mRNA encoding a fibroblast activation protein (FAP)-specific CAR to reprogram host immune cells in vivo and target cancer-associated fibroblasts within the tumor stroma. In multiple solid tumor mouse models, this approach, combined with chemotherapeutic agents and immune checkpoint inhibitors, achieved significant tumor regression and induced durable, antigen-specific immune memory. Incorporation of m 6 A-modified CAR mRNA accelerated and amplified antitumor responses, while blockade of the macrophage migration inhibitory factor (MIF)-CD74 axis further improved tumor control by alleviating immune suppression. In patient-derived xenograft models, HOX family transcription factors were implicated in treatment resistance, highlighting a potential biomarker and therapeutic target. The evidence from this study demonstrates that targeting the tumor microenvironment with a controllable mRNA-modulated strategy achieves substantial antitumor efficacy and holds significant potential to enhance the applicability and acceptance of CAR-T cell therapy across a variety of cancers.

Purpose Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225 Ac or 131 I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). Methods We studied the biodistribution and tumour uptake of [ 131 I]I-GMIB-4AH29 and [ 225 Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [ 131 I]I-GMIB-4AH29 and [ 225 Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [ 225 Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [ 225 Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. Results The biodistribution showed high tumour uptake of [ 131 I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [ 225 Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [ 131 I]I-GMIB-4AH29 or [ 225 Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [ 225 Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [ 225 Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. Conclusion [ 225 Ac]Ac-DOTA-4AH29 and [ 131 I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [ 225 Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.

Fibroblast activation protein (FAP) has emerged as a highly promising target for cancer diagnostic imaging and targeted radionuclide therapy. To exploit the therapeutic potential of suitably radiolabeled FAP inhibitors (FAPIs), this study presents the design and synthesis of a series of FAPI dimers to increase tumor uptake and retention. Preclinical evaluation and a pilot clinical PET imaging study were conducted to screen the lead compound with the potential for radionuclide therapy. Methods Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [ 68 Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. Results The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [ 68 Ga]Ga-LNC1013 had persistent tumor retention for at least 4 h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [ 68 Ga]Ga-LNC1013 was 8.24E-03 mSv/MBq. The human biodistribution of [ 68 Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [ 68 Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18 F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [ 68 Ga]Ga-FAPI-46 decreased over time, whereas [ 68 Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4 h post-injection. Conclusion Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [ 68 Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [ 68 Ga]Ga-FAPI-46 and 18 F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.

Photoimmunotherapy (PIT), carried out using an Ab conjugated to the near infrared dye IRDye700DX, is achieving significant success in target‐specific elimination of cells. Fibroblast activation protein alpha (FAP‐α) is an important target in cancer because of its expression by cancer‐associated fibroblasts (CAFs) as well as by some cancer cells. Cancer‐associated fibroblasts that express FAP‐α have protumorigenic and immune suppressive functions. Using immunohistochemistry of human breast cancer tissue microarrays, we identified an increase of FAP‐α+ CAFs in invasive breast cancer tissue compared to adjacent normal tissue. We found FAP‐α expression increased in fibroblasts cocultured with cancer cells. In proof‐of‐principle studies, we engineered human FAP‐α overexpressing MDA‐MB‐231 and HT‐1080 cancer cells and murine FAP‐α overexpressing NIH‐3T3 fibroblasts to evaluate several anti‐FAP‐α Abs and selected AF3715 based on its high binding affinity with both human and mouse FAP‐α. After conjugation of AF3715 with the phthalocyanine dye IR700, the resultant Ab conjugate, FAP‐α‐IR700, was evaluated in cells and tumors for its specificity and effectiveness in eliminating FAP‐α expressing cell populations with PIT. Fibroblast activation protein‐α‐IR700‐PIT resulted in effective FAP‐α‐specific cell killing in the engineered cancer cells and in two patient‐derived CAFs in a dose‐dependent manner. Following an intravenous injection, FAP‐α‐IR700 retention was three‐fold higher than IgG‐IR700 in FAP‐α overexpressing tumors, and two‐fold higher compared to WT tumors. Fibroblast activation protein‐α‐IR700‐PIT resulted in significant growth inhibition of tumors derived from FAP‐α overexpressing human cancer cells. A reduction of endogenous FAP‐α+ murine CAFs was identified at 7 days after FAP‐α‐IR700‐PIT. Fibroblast activation protein‐α‐targeted near infrared PIT presents a promising strategy to eliminate FAP‐α+ CAFs. In our studies we first demonstrated increased expression of FAP‐α CAFs in human breast cancer tissue microarrays and in human mammary fibroblasts (HMFs) co‐cultured with human breast cancer cells. Next, in proof‐of‐principle studies, we engineered FAP‐α overexpressing human breast cancer MDA‐MB‐231 and human fibrosarcoma HT‐1080 cells to demonstrate successful elimination of FAP‐α expressing cell populations in tumors in vivo with NIR‐PIT. NIR‐PIT resulted in significant and selective growth inhibition of FAP‐α overexpressing tumors, and effective depletion of endogenous FAP‐α murine CAFs. The combination of target‐specific antibody binding with localized NIR exposure of the tumor avoided the off‐target toxicity associated with systemic FAP‐α‐targeted therapies.

Intervertebral disc degeneration (IDD) is a primary cause of low back pain, with the development of new blood vessels being a key pathological feature. Fibroblast activation protein‐alpha (FAP‐α), a member of the Type II serine protease family, possesses dipeptidase and collagenase activities and is closely linked to angiogenesis. Bioinformatics and immunohistochemical analysis revealed elevated FAP‐α expression and increased angiogenesis in degenerated cartilage endplate (CEP). Co‐culture of FAP‐α‐silenced CEP cells or conditioned media with human umbilical vein endothelial cells (HUVECs) demonstrated a reduction in hypoxia‐inducible factor‐α (HIF‐α) levels, vascular endothelial growth factor (VEGF)‐A and PI3K/AKT phosphorylation, which impaired HUVEC migration and tube formation. Conversely, FAP‐α overexpression enhanced angiogenesis via the PI3K/AKT/HIF‐α/VEGF‐A signalling pathway. In rats with IDD induced by lumbar instability, FAP‐α inhibitors reduced angiogenesis and ossification of the CEP, thereby delaying IDD progression associated with CEP degeneration. Genetic deletion of FAP further slowed IDD progression. Collectively, these findings provide compelling evidence that FAP‐α accelerates IDD by promoting angiogenesis, which disrupts disc homeostasis. Targeting FAP‐α may offer a novel therapeutic approach for mitigating IDD. Schematic illustration showing that FAP‐α promoted angiogenesis, cytokine release and ECM degradation in the CEP degeneration of the intervertebral disc through upregulating the PI3K/Akt/HIF‐1α/VEGFA pathway.

Background [ 68 Ga]Ga-labeled fibroblast activation protein inhibitor ([ 68 Ga]Ga-FAPI) PET/CT has shown promising potential in predicting pathological complete response (pCR) in patients with breast cancer (BC). However, current literature lacks comprehensive data addressing molecular subtype-specific variations. This study aims to evaluate the predictive value of [ 68 Ga]Ga-FAPI-04 PET/CT across different BC molecular subtypes. Methods This preliminary study enrolled 66 patients with clinical stage II-III BC scheduled for neoadjuvant chemotherapy (NAC). Patients underwent [ 68 Ga]Ga-FAPI-04 PET/CT at baseline (PET1), after two NAC cycles (PET2), and presurgery (PET3). The maximum standardized uptake value (SUVmax) and its percentage change from baseline (ΔSUVmax) were calculated for the primary tumors. Pathological response was assessed postsurgery. Patients were stratified into three molecular subtypes: hormone receptor-positive/HER2-negative (HR+/HER2−), HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Receiver operating characteristic (ROC) curve analysis was utilized to evaluate the predictive performance of FAPI parameters for pCR. Results Among the 66 patients, 21 (31.8%) achieved pCR, with rates varying significantly across molecular subtypes ( P  = 0.002). Baseline [ 68 Ga]Ga-FAPI-04 uptake (SUVmax1) was significantly higher in HER2+ tumors (17.98 ± 6.34) compared to HR+/HER2− (14.37 ± 4.11) and TNBC tumors (15.00 ± 5.25) ( P  = 0.043). The predictive value of [ 68 Ga]Ga-FAPI-04 parameters for pCR was highly dependent on molecular subtype. In HER2+ tumors, early response assessment was most effective, with ΔSUVmax1 (change after two cycles) being the strongest predictor (area under the curve [AUC] = 0.799). A cutoff of − 69.49% yielded 85.7% sensitivity and 72.7% specificity. For TNBC, late-phase parameters demonstrated exceptional accuracy, with SUVmax3 (presurgery) achieving near-perfect discrimination (AUC = 0.967). A cutoff of ≤ 2.19 provided 100% sensitivity and 95.5% specificity. In HR+/HER2− tumors, late-phase parameters were most predictive, with SUVmax3 showing excellent performance (AUC = 0.948). A cutoff of ≤ 1.58 yielded 75.0% sensitivity and 91.7% specificity. Conclusion The predictive efficacy of [ 68 Ga]Ga-FAPI-04 PET/CT for pCR demonstrates substantial variability across BC molecular subtypes. These findings underscore the potential of [ 68 Ga]Ga-FAPI-04 PET/CT to inform subtype-specific, personalized treatment approaches.

Pulmonary fibrosis arises from a dysregulated wound-healing response in which activated fibroblasts drive excessive extracellular matrix deposition and irreversible lung architectural distortion. Conventional high-resolution computed tomography (HRCT) detects largely established structural damage, limiting opportunities for early intervention. The fibroblast activation protein (FAP), a membrane-bound serine protease expressed on activated fibroblasts, presents a potential molecular target for imaging active fibrogenesis. The advent of fibroblast activation protein inhibitor (FAPI)–based radiotracers for positron emission tomography (PET) has been developed to visualize FAP expression in vivo. This review traces the translational continuum from FAP biology through radiotracer development to clinical application of FAPI-PET/CT in interstitial lung diseases, summarising preclinical and emerging human studies investigating FAPI PET/CT in interstitial lung diseases, highlighting preliminary evidence for the detection of early fibroblast activation, potential risk stratification, and monitoring of therapy response. We also discuss the functional heterogeneity of FAP-expressing fibroblast subsets and the interpretive challenges this poses for FAPI imaging. The review also considers early translational work on FAPI-based theranostics, combining diagnostic imaging with fibroblast-targeted radioligand approaches. While FAPI-PET/CT shows promise as a tool for characterizing fibrogenic activity, current evidence remains limited, and prospective studies are needed to clarify its clinical utility and potential role in guiding personalized interventions. Graphical Abstract

Purpose High-grade meningiomas have high recurrence rates and limited prognosis. Radioligand therapies are approved in extracranial malignancies, but their value in brain tumours including meningiomas is unclear, as data on target expression is scarce. Methods CNS WHO grade 2 and 3 meningioma samples were immunohistochemically stained for somatostatin receptor 2a (SSTR2a), fibroblast activation protein (FAP), and human epidermal growth factor receptors 2/3 (HER2/HER3). Target expression was correlated with (epi-)genetic tumour subtyping by DNA methylation analysis, genetic alterations, and survival. Results Meningioma samples of 58 patients were included. SSTR2a expression (membranous/cytoplasmic) was observed in 43/55 (78.2%), and FAP expression in 15/58 (25.9%) evaluable samples, with HER2 and HER3 expression in one specimen each (1.7%). Membranous SSTR2a expression was strong in 18 (32.7%), intermediate in 12 (21.8%), and weak in 11 (20.0%) samples. While SSTR2a expression was more homogenous and mainly seen in regions with higher cellularity, FAP immunoreactivity was predominantly seen in tumour stroma and regions of lower cellularity. SSTR2a immunoreactivity was associated with TRAF7 wildtype status ( p  = 0.034). FAP expression was more frequent in meningiomas of CNS WHO grade 3 (vs. CNS WHO 2; p  < 0.001), and samples with NF2 mutations ( p  = 0.032) or CDKN2A/B deletions ( p  = 0.013) compared to wildtype. FAP and SSTR2a expression (present vs. absent) were not associated with overall survival ( p  > 0.05). Conclusion SSTR2a and FAP are expressed in high-grade meningioma samples to a variable extent, and differences across meningioma subtypes underscore the need for biomarkers to improve patient selection. Spatial heterogeneity of target expression should be considered in radioligand therapy design.

This study investigates the role of Fibroblast Activation Protein (FAP)-positive cancer-associated fibroblasts (FAP+CAF) in shaping the tumor immune microenvironment, focusing on its association with immune cell functionality and cytokine expression patterns. Utilizing immunohistochemistry, we observed elevated FAP+CAF density in metastatic versus primary renal cell carcinoma (RCC) tumors, with higher FAP+CAF correlating with increased T cell infiltration in RCC, a unique phenomenon illustrating the complex interplay between tumor progression, FAP+CAF density, and immune response. Analysis of immune cell subsets in FAP+CAF-rich stromal areas further revealed significant correlations between FAP+ stroma and various T cell types, particularly in RCC and non-small cell lung cancer (NSCLC). This was complemented by transcriptomic analyses, expanding the range of stromal and immune cell subsets interrogated, as well as to additional tumor types. This enabled evaluating the association of these subsets with tumor infiltration, tumor vascularization and other components of the tumor microenvironment. Our comprehensive study also encompassed cytokine, angiogenesis, and inflammation gene signatures across different cancer types, revealing heterogeneous cellular composition, cytokine expressions and angiogenic profiles. Through cytokine pathway profiling, we explored the relationship between FAP+CAF density and immune cell states, uncovering potential immunosuppressive circuits that limit anti-tumor activity in tumor-resident immune cells. These findings underscore the complexity of tumor biology and the necessity for personalized therapeutic and patient enrichment approaches. The insights gathered from FAP+CAF prevalence, immune infiltration, and gene signatures provide valuable perspectives on tumor microenvironments, aiding in future research and clinical strategy development.