Tumours contain many fibroblasts, endothelial cells, and leukocytes that are emerging as therapeutic targets complementary to targeting genetically unstable cancer cells. Immunotherapies directed towards this tumour microenvironment (TME) are increasingly effective. Targeting the endothelium has shown success, particularly in hepatocellular carcinoma (HCC). Cancer-associated fibroblasts (CAFs) are also attracting novel nascent therapeutic approaches, and fibroblast activation protein (FAP), which is specific to activated mesenchyme, is prominent amongst CAF markers. This review places emphasis upon FAP, human HCC, and FAP-targeting approaches for therapeutic benefit, including FAP inhibitors, radioligand therapy, T cell and antibody-dependent cytotoxicity/immunotherapy, and FAP-activated prodrugs.

There are no ideal non-invasive tests for assessing the severity of liver fibrosis in people with metabolic dysfunction-associated steatotic liver disease (MASLD) and class 3 obesity, where body habitus often makes imaging technically challenging. This study aimed to assess the applicability and diagnostic performance of two-dimensional shear wave elastography (2D-SWE), alongside several serum-based liver fibrosis scoring methods, in individuals with class 3 obesity. A cross-sectional study was conducted in patients aged ≥18 years and with a body mass index (BMI) ≥ 40 kg/m² who were participants in a publicly funded multidisciplinary weight management program in South Western Sydney. The 2D-SWE was performed using the ElastQ Imaging (EQI) procedure with the Phillips EPIQ Elite series ultrasound. An EQI Median value of ≥6.43 kPa was taken as a cutoff score for significant fibrosis, and the scan was considered valid when the liver EQI IQR/Med value was <30%. The Fibrosis-4 (FIB-4) index, AST-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS), and circulating fibroblast activation protein index (FAP index) were calculated from fasting blood samples. The participants (n = 116; 67.2% female) were aged 47.2 ± 12.9 years, with BMI 54.5 ± 11.0 kg/m². EQI Median values were obtained for 97.4% (113/116) of the 2D-SWE scans, and 91.4% (106/116) of the scans were considered valid. The EQI Median values exhibited a moderately positive correlation with the FIB-4 index (r = 0.438; p < 0.001) and a weakly positive correlation with the APRI (r = 0.388; p < 0.001), NFS (r = 0.210; p = 0.036) and FAP index (r = 0.226; p = 0.020). All liver fibrosis scores were positively correlated with one another. Among those referred for a liver biopsy based on the 2D-SWE and serum scores, half (11/22) underwent liver biopsy, and their 2D-SWE scores exhibited 72.7% accuracy (sensitivity: 71.4%; specificity: 75%) in detecting significant fibrosis. Our results show that 2D-SWE is a feasible, non-invasive test to assess liver fibrosis among people with class 3 obesity. Further research is needed to assess how 2D-SWE can be used alongside existing serum-based risk scores to reliably detect significant fibrosis, which would potentially reduce the need for invasive liver biopsy.

Background: Noninvasive fibrosis testing is crucial for metabolic dysfunction–associated steatotic liver disease (MASLD) management. This study evaluated a marker of activated mesenchymal fibrogenic cells, circulating fibroblast activation protein (cFAP), in a novel diagnostic algorithm, FAP Index, for patients with MASLD. Methods: Two retrospective cohorts recruited from tertiary hepatology clinics were studied as training ( n = 160) and external validation cohorts ( n = 332), with prevalence of histologic advanced fibrosis (F3–F4) of 20% and 11%, respectively. cFAP was measured using our rapid single‐step FAP‐specific microplate enzyme assay. A predictive model, FAP Index, containing age, type 2 diabetes, alanine transaminase, and ordinal cFAP was developed using logistic regression; then, its diagnostic accuracy was evaluated. Results: FAP Index AUROC for advanced fibrosis was 0.875 (95% CI: 0.813–0.938) in the training cohort and 0.841 (95% CI: 0.776–0.906) in the validation cohort. Low cutoff 0.157 (sensitivity 84.3%, negative predictive value 95%) and high cutoff 0.695 (specificity 99.2%, positive predictive value 92.9%) values excluded and predicted advanced fibrosis, respectively. FAP Index following FIB‐4 reduced the frequency of indeterminate results by more than one‐third compared to FIB‐4 alone. FAP Index following NFS (NAFLD Fibrosis Score) reduced the frequency of indeterminate results by ~70% compared to NFS alone. Conclusion: Without a need for elastography, applying FAP Index following FIB‐4 or NFS can facilitate accurate risk stratification of patients by greatly reducing the frequency of indeterminate results compared to FIB‐4 or NFS alone, without compromising negative predictive value. Thus, FAP Index is a novel, fibrogenesis‐relevant, rapid, robust diagnostic tool suited to increasing the efficiency of liver fibrosis triage in primary care.

This paper provides first-time evidence of covalent attachment of fluorescent molecules to plasma polymerised nanoparticles for diagnostic and therapeutic applications.