Purpose <p>Prostate-specific membrane antigen (PSMA) expression has been observed in a subset of soft tissue sarcomas, mainly in the neovascular endothelial cells. This feasibility study aimed to evaluate PSMA expression and PSMA PET/CT imaging in metastatic soft tissue sarcoma, providing important insights for potential future exploration of PSMA-targeted radioligand therapy.</p> Methods <p>This prospective single-center study included adult patients with metastatic soft tissue sarcoma, with measurable disease (lesion diameter &gt; 1&#xa0;cm), available biopsy/resection material, ECOG/WHO performance status of 0–2 and either no prior systemic treatment, progressive disease during/after treatment, or stable disease/partial response with the last dose &gt; 8 weeks prior. Immunohistochemical PSMA staining was performed on previously obtained biopsy or resection material. In case of high PSMA expression, a [¹⁸F]-JK-PSMA-7 PET/CT scan evaluated tracer uptake, with adequate uptake defined as SUV_max &gt; 8.</p> Results <p>Of 25 included patients, 11 (44%) had high PSMA expression: 4/11 leiomyosarcomas, 3/4 dedifferentiated liposarcomas, 2/5 undifferentiated pleomorphic sarcomas, 1/2 myxofibrosarcomas and 1/1 malignant peripheral nerve sheath tumour. Five of 11 patients agreed to a [¹⁸F]-JK-PSMA-7 PET/CT, of which 3 had lesions that showed adequate tracer uptake (SUV_max 10.7–16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUV_max = 3.8; range 0.5–16.7), indicating that these patients are unlikely to benefit sufficiently from PSMA-targeted therapy. The study was therefore terminated prematurely.</p> Conclusion <p>PSMA expression and PSMA tracer uptake in metastatic soft tissue sarcoma were highly heterogeneous. A deeper understanding of PSMA biology and improved patient selection criteria are essential for future application of PSMA-targeted radioligand therapy in this disease.</p> Trial registration <p>: clinicaltrials.gov, NCT05522257. Registered 31-08-2022.</p>