Beyond Prostate-Specific Membrane Antigen: The Design and Future of Novel Radiopharmaceuticals Targeting the Tumor Microenvironment

Lu] Lu-PSMA-617 therapy. However, heterogeneous antigen expression, acquired resistance, lineage plasticity, and nonresponding lesions show that a cancer cell-centric strategy cannot fully address the ecological complexity of advanced malignancy. The tumor microenvironment (TME) offers a complementary target space because stromal, vascular, immune, and chemokine-driven niches are functionally required for tumor growth and are often more genomically stable than malignant cells. This review synthesizes the biological rationale, radiochemical design, clinical translation, and current limitations of TME-targeted radiopharmaceuticals, focusing on fibroblast activation protein (FAP), integrins, and the CXCR4/CXCL12 axis. The authors discuss first-generation FAP inhibitor (FAPI) tracers and therapeutic limitations caused by short tumor residence, and then compare next-generation strategies, including dimerization, multimerization, albumin-binding motifs, peptide-based ligands such as FAP-2286, and newer FAPI-derived therapeutic constructs. They also reassess RGD-based integrin targeting as a clinically informative but heterogeneous angiogenesis platform, and summarize CXCR4-directed pentixather therapy in hematological malignancies and selected solid tumor models. Finally, they examine radionuclide selection, dosimetry, patient selection, and combination strategies with chemotherapy, antiangiogenic therapy, immune checkpoint blockade, cytokine therapy, and cell-based therapy. TME-targeted radiopharmaceuticals are unlikely to replace tumor cell-directed theranostics; rather, their most important role may be to reshape resistant tumor ecosystems and rationally extend precision radionuclide therapy beyond single-antigen paradigms.