Theranostics in Sarcoma: A Critical Review of Current Evidence and Future Potential

Sarcomas are rare, heterogeneous malignancies with over 100 subtypes and limited effective therapies in advanced stages. Theranostics, a strategy that combines diagnostic imaging and targeted radionuclide therapy using the same molecular target, has revolutionized care in cancers, including prostate and neuroendocrine tumors. This review evaluates the current evidence and future potential of theranostic applications in sarcoma. A comprehensive literature search was conducted across PubMed, Google Scholar, and clinicaltrials.gov for studies published between January 2010 and August 2025. Search terms included “theranostics,” “radionuclide,” “molecular imaging,” “sarcoma,” and molecular targets such as PSMA, FAPI, SSTR, PDGFR, and TEM-1. Eligible articles included clinical trials, cohort studies, and systematic reviews. Case reports were included only when higher-level evidence was lacking. Key theranostic targets in sarcoma include FAP, PSMA, SSTR, and PDGFR. Among these, FAP-directed agents demonstrate the most clinical maturity, with improved diagnostic performance compared to 18F-FDG and early evidence of disease control with 90Y/177Lu-labeled therapies. PSMA and SSTR expression in sarcomas is more variable and localized to tumor vasculature, with case-level therapeutic use and limited efficacy data. PDGFR and emerging targets, such as TEM-1, show biological promise but remain under investigation in early-phase studies. Theranostics represents a promising approach to individualized sarcoma treatment, with FAP-targeted agents showing the most advanced clinical development. FAP-based imaging improves lesion detection compared to standard 18F-FDG PET, and early therapeutic trials suggest disease control in select patients. However, broader validation and regulatory approval are needed before clinical integration. Theranostics represents a promising precision-medicine paradigm for sarcoma, linking diagnostic PET imaging with targeted radioligand therapy targeting a shared molecular target. With more than 100 histologic subtypes and limited effective treatment options in advanced disease, theranostics may provide a future therapeutic avenue for selected patients. Among currently investigated platforms, fibroblast activation protein-directed approaches are the most clinically advanced. 68Ga FAPI PET has demonstrated superior lesion detection compared with 18 F FDG across multiple sarcoma subtypes, and early studies of 90Y- and 177Lu-labeled FAPI agents report disease stabilization in selected patients with advanced disease, supporting biological and technical feasibility. In contemporary practice, FAP-directed imaging is best integrated within investigational frameworks to identify candidates for radioligand therapy, refine trial selection, and enable response monitoring in FAP-avid sarcomas. Other targets, including PSMA, SSTR, and PDGFR, remain exploratory and require prospective validation before clinical translation. Standard sarcoma management continues to rely on guideline-directed multimodality care, including surgery, radiation, and subtype-specific systemic therapy, with theranostic strategies currently limited to clinical trials or selected refractory settings. Broader clinical adoption will depend on prospective studies demonstrating meaningful clinical benefit, optimized dosimetry, and regulatory approval.