Targeted Radiopharmaceuticals Are Reshaping Precision Cancer Therapy

Target-specific radiopharmaceuticals use molecular targeting vectors to selectively localize cancer cells, and by pairing matched diagnostic and therapeutic radionuclides they provide a personalized theranostic approach to cancer therapy. A new review published in Holistic Integrative Oncology argues that these agents now constitute an essential framework for delivering precision medicine in nuclear oncology, with FDA-approved therapeutic radiopharmaceuticals and their corresponding imaging probes offering a validated roadmap for developing novel targeted radiotracers. A substantial number of new target-specific molecular probes are currently being evaluated in clinical trials, and the review traces their progress from preclinical research to clinical translation across a series of molecular targets.

The logic of theranostics is straightforward: combine tumor-specific diagnostic imaging with subsequent targeted radionuclide therapy using the same molecular target. Therapeutic radionuclides fall into three classes: beta emitters, alpha emitters, and Auger electron emitters. Beta-emitting radionuclides remain the mainstay of targeted radionuclide therapy because their intermediate particle range allows delivered radiation to reach not only the targeted cells but also adjacent tumor cells that may not have taken up the agent, making them particularly suitable for larger tumor volumes or metastatic deposits. FDA-approved agents labeled with lutetium-177, which has a half-life of 6.7 days, and yttrium-90, with a half-life of 64.1 hours, have been successfully translated into clinical practice, most prominently Lutathera, or lutetium-177 DOTATATE, and Pluvicto, or lutetium-177 PSMA-617.

Alpha emitters operate on a different principle. They emit over short ranges of 50 to 100 micrometers and carry a high linear energy transfer, which enables precise eradication of microscopic disease foci while minimizing collateral damage to surrounding healthy tissue. Because alpha particles have greater cytotoxic potency than beta particles, targeted alpha therapy is described in the review as a cutting-edge paradigm in precision oncology offering potent and highly selective radiopharmaceutical strategies. On the imaging side, positron emission tomography using radiopharmaceuticals with high affinity for designated molecular targets enables whole-body visualization of lesion distribution and noninvasive determination of target expression levels, supporting patient stratification and individualized clinical decisions.

The most mature target is prostate-specific membrane antigen, a type II transmembrane glycoprotein highly expressed in prostate cancer cells and in the neovascular endothelial cells of various solid tumors. PSMA expression in malignant cells is 100- to 1000-fold greater than in normal cells, correlates positively with tumor grade and stage, and is further upregulated in advanced and castration-resistant disease. Several PSMA imaging agents are approved, including gallium-68 PSMA-11, fluorine-18 rhPSMA-7.3, and fluorine-18 DCFPyL, while fluorine-18 PSMA-1007 has been approved for clinical use in several European countries. Guidelines indicate gallium-68 PSMA-11 PET/CT for high-risk prostate cancer staging, biochemical recurrence evaluation, and metastatic castration-resistant disease management, and a meta-analysis reported an overall detection rate of 76 percent for PSMA PET in biochemical recurrence, falling to 45 percent for PSA values below 0.5 nanograms per milliliter.

PSMA imaging also serves as a predictive tool for selecting patients for radioligand therapy. The VISION trial, a randomized open-label multicenter phase 3 trial in 831 patients with metastatic castration-resistant prostate cancer, found that adding lutetium-177 PSMA-617 to standard care was associated with significant improvement in both imaging-based progression-free survival and overall survival, alongside delayed symptomatic skeletal events, preserved quality of life, pain control, and retarded biochemical progression. On the alpha side, actinium-225 PSMA therapy, with a half-life of 9.92 days, is reported as effective and safe with manageable toxicity in disease refractory to lutetium-177 PSMA, showing potential even for advanced patients with limited options.

Gallium-68 labeled somatostatin analogs DOTATOC, DOTATATE, and DOTANOC offer significant accuracy improvements over standard morphological imaging, with pooled meta-analytic sensitivities of 92 percent for DOTATOC and 90.9 percent for DOTATATE in detecting neuroendocrine tumors. In a meta-analysis spanning 2266 patients across 24 studies, DOTA-somatostatin analog PET/CT altered clinical management in 36 percent of patients. On the therapeutic side, the randomized phase 3 NETTER-1 trial assessed lutetium-177 DOTATATE in well-differentiated metastatic midgut neuroendocrine tumors and estimated 20-month progression-free survival at 65.2 percent with an objective response rate of 18 percent. SSTR antagonists such as gallium-68 NODAGA-JR11 have pushed imaging further, achieving higher sensitivity than DOTATATE, 91.7 percent versus 77.2 percent, in a prospective bi-center study of metastatic well-differentiated tumors.

Fibroblast activation protein, highly expressed on cancer-associated fibroblasts in the tumor stroma and present in over 90 percent of malignant epithelial tumors while low or negligible in most normal tissues, has become a pivotal target aimed at the tumor microenvironment. Quinoline-based FAP inhibitors such as gallium-68 FAPI-04 show rapid tracer accumulation and high tumor-to-background ratios, and head-to-head studies demonstrated superior diagnostic efficacy over fluorine-18 FDG PET in detecting primary and metastatic lesions, particularly in the liver, peritoneum, and brain. The derivative FAPI-46 achieves prolonged tumor accumulation and increased retention suited to therapy; a single-center phase 2 trial found gallium-68 FAPI-46 PET achieved positive predictive values of 80 to 100 percent for detecting multiple cancers. Early therapeutic work includes a preliminary dose-escalation study in which 18 patients with advanced malignancies received lutetium-177 FAPI-46 over 36 cycles with initial findings indicating potential feasibility and a manageable safety profile, while yttrium-90 FAPI-46 treatment confirmed disease control in 8 of 21 patients with progressive metastatic malignancies, associated with prolonged overall survival.

The cyclic peptide FAP-2286 extends this program, with lutetium-177 labeled retention exceeding 72 hours in tumors. First-in-human therapy in 11 patients with end-stage pancreatic, breast, ovarian, and colorectal cancers used doses of 5.8 plus or minus 2.0 gigabecquerels and demonstrated a favorable safety profile with acceptable cumulative doses and alleviation of disease-related symptoms. A subsequent prospective single-arm trial in gastrointestinal tumors enrolled 14 patients, of whom 4 achieved stable disease and 10 exhibited progressive disease, substantiating safety and tolerability while underscoring the need for larger studies. The review also surveys emerging targets including chemokine receptor type 4, where gallium-68 Pentixafor PET/CT showed consistently high uptake in multiple myeloma and lymphomas and detected a greater disease extent than FDG in 68 percent of myeloma patients, and carbonic anhydrase IX, where new small-molecule tracers show high diagnostic efficacy for metastatic clear cell renal cell carcinoma though limited value for primary tumors.

Newer targets are following the same path. Trop2, a transmembrane glycoprotein highly expressed in various solid tumors with low expression in normal tissues, is now served by immuno-PET tracers that visualize heterogeneous expression; gallium-68 NOTA-T4 identified more brain metastases than FDG owing to lower background uptake, and its uptake correlated positively with TROP2 tumor proportion scores. Glypican-3, overexpressed in 70 to 80 percent of hepatocellular carcinomas but negligible in healthy liver, supports both imaging and therapy development, including actinium-225 and lutetium-177 labeled agents that reduced tumor burden in preclinical models. Claudin 18.2 tracers for gastrointestinal malignancies achieved 93.3 percent accuracy for detecting positive tumors in a 16-patient study. The review closes with candid challenges: radionuclide supply is a primary bottleneck, with actinium-225 production currently sufficient to treat only a few hundred patients annually, GMP manufacturing poses technical and regulatory hurdles, and off-target toxicity in healthy organs remains a major obstacle that will demand deeper mechanistic understanding, defined dose-effect relationships, and individualized mitigation strategies before multi-omics-guided personalized design and novel radionuclides can fully reshape precision cancer therapy.

Subject of Research: Target-specific radiopharmaceuticals for cancer theranostics

Article Title: Advancements in nuclear medicine for target-specific cancer theranostics

Article References: Chen, X., Shi, F., Sun, Y., Fu, Q., Chen, X., Han, C., Wang, M., Pang, X., & Zhao, X. (2026). Advancements in nuclear medicine for target-specific cancer theranostics. Holistic Integrative Oncology, 5(1), Article 90. https://doi.org/10.1007/s44178-026-00312-6

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00312-6

Keywords: radiopharmaceuticals, theranostics, targeted radionuclide therapy, PSMA, fibroblast activation protein, alpha emitters, PET imaging, neuroendocrine tumors, CXCR4, Trop2, radionuclide supply, precision oncology