Radioligand therapy (RLT) is a precision cancer treatment that combines a tumor-targeting molecule (ligand) with a therapeutic radioactive isotope.
After being infused into the bloodstream, it seeks out and binds to specific proteins on cancer cells.
Radioligand therapy (RLT) is a targeted cancer treatment that combines a tumor-specific ligand with a therapeutic radionuclide to deliver cytotoxic radiation directly to cancer cells while sparing surrounding tissues.
RLT agents consist of three components: (1) a targeting moiety (peptide, small molecule, or antibody) that binds a tumor-expressed receptor, (2) a chelator that securely binds the radionuclide, and (3) a therapeutic radionuclide emitting beta particles (¹⁷⁷Lu), alpha particles (²²⁵Ac, ²²³Ra), or Auger electrons (¹⁶¹Tb).
Beta emitters like ¹⁷⁷Lu have a tissue penetration range of ~2 mm, producing single-strand DNA breaks, while alpha emitters like ²²⁵Ac cause more potent double-strand DNA breaks with a shorter range (~50–100 μm).
The localized radiation destroys the tumor from the inside out while largely sparing healthy surrounding tissue.
RLT relies on the concept of theranostics (therapeutics + diagnostics):It follows a theranostic paradigm — diagnostic imaging first confirms target expression, then the same molecular target is used for therapy.
Before administering the therapy, a PET scan using a similar tracer to confirm that the specific cancer cells express the target protein (like PSMA for prostate cancer or somatostatin receptors for neuroendocrine tumors).
This ensures the treatment will effectively locate and bind to the tumors.
Types of Cancer TreatedCurrently, FDA-approved radioligand therapies are primarily used for:Prostate Cancer: Targets the Prostate-Specific Membrane Antigen (PSMA).Neuroendocrine Tumors (NETs): Targets somatostatin receptors using peptide receptor radionuclide therapy (PRRT).Thyroid Cancer: Historical use of radioactive iodine, which naturally accumulates in the thyroid.
Highly targeted, enabling the treatment of both primary tumors and metastatic sites across the body.
It often has fewer systemic side effects than traditional chemotherapy.
Common Side Effects: Because the radioactive element travels through the body, some patients may experience mild fatigue, nausea, dry mouth, or temporary lowering of blood cell counts.
Two radioligand therapies are currently in widespread clinical use:
¹⁷⁷Lu-DOTATATE (Lutathera) — Approved for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults and pediatric patients ≥12 years.
Administered at 7.4 GBq (200 mCi) IV every 8 weeks for 4 doses, with concurrent amino acid infusion for nephroprotection.
The NETTER-2 trial has also established its role as first-line treatment in advanced grade 2–3 GEP-NETs.
¹⁷⁷Lu-PSMA-617 (Pluvicto) — Approved for PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) in patients treated with androgen receptor pathway inhibitor (ARPI) therapy who have received or are appropriate to delay taxane-based chemotherapy.
The VISION trial demonstrated improved rPFS (8.7 vs. 3.4 months) and OS (15.3 vs. 11.3 months) Administered at 7.4 GBq every 6 weeks for up to 6 treatments.
Additional agents include radium-223 for CRPC with symptomatic bone metastases and ⁹⁰Y-ibritumomab tiuxetan for non-Hodgkin lymphoma (rarely used).
Expanding Clinical Evidence
Earlier-line prostate cancer: The PSMAfore trial extended evidence to taxane-naïve mCRPC, and the PSMAddition trial showed improved rPFS when Lu-PSMA was added to ADT plus ARPI in metastatic hormone-sensitive prostate cancer (mHSPC).
The ENZA-p trial demonstrated an OS benefit combining Lu-PSMA with enzalutamide.
²²⁵Ac-PSMA (alpha therapy) has shown PSA decline ≥50% in 57% of heavily pretreated mCRPC patients in the WARMTH study, though xerostomia is highly prevalent at 68–95%. (dual beta/Auger emitter) is entering clinical development for improved targeting of small lesions.
¹⁶¹Tb-PSMA (dual beta/Auger emitter) is entering clinical development for improved targeting of small lesions.
Novel targets under investigation include fibroblast activation protein (FAP), CXCR4, CAIX, and gastrin-releasing peptide receptor (GRPR), with over 400 clinical trials registered as of 2025.
Appropriate patient selection requires confirmation of target expression via companion diagnostic imaging for neuroendocrine tumors and PSMA PET/CT for prostate cancer.
Patients with dominant PSMA-negative lesions are not recommended for Lu-PSMA-617 therapy.
Adequate bone marrow, renal, and hepatic function are prerequisites for both approved agents.
Infrastructure Requirements