The core logic of the approach is deceptively simple. A target-specific ligand is first labeled with a positron-emitting radionuclide such as gallium-68 or fluorine-18 and used in PET imaging to verify that a patient’s lesions actually express the target and that tracer distributes across the whole body. Only then is a therapeutic radionuclide—commonly lutetium-177, actinium-225, or yttrium-90—attached to the same or a closely related ligand and administered, delivering cytotoxic radiation with relative selectivity to tumor tissue. The authors emphasize that imaging in this context is not an adjunct to therapy but the starting point and foundation of the entire treatment pathway. Target stability, interlesional heterogeneity, physiologic uptake in normal tissues, and the feasibility of dosimetric assessment all directly influence benefit and risk, which is why pretreatment molecular imaging has become an indispensable gatekeeping step rather than a diagnostic formality.

PSMA stands out as the most mature system, and its success rests on elegant biology. PSMA is a type II transmembrane glycoprotein with a large extracellular domain and ligand-induced internalization, making it highly accessible to small molecules built on the Glu-urea-Lys scaffold. Expression is markedly upregulated in prostate cancer, particularly in high-risk, metastatic, and castration-resistant disease. The pivotal phase III VISION trial demonstrated that lutetium-177-labeled PSMA-617 plus standard care extended median radiographic progression-free survival from 3.4 to 8.7 months and median overall survival from 11.3 to 15.3 months in patients with PSMA-positive metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibition and taxane chemotherapy. Subsequent real-world studies and meta-analyses have consistently supported both efficacy and an acceptable safety profile, cementing beta-emitter PSMA therapy as established clinical practice rather than an experimental strategy.

Yet the beta emitter is not the end of the story. Beta particles have an intermediate tissue range and low linear energy transfer, producing a cross-fire effect suited to multifocal metastatic disease but potentially inadequate for microscopic residual lesions or tumors with heterogeneous uptake. Actinium-225 offers a different physics: an extremely high linear energy transfer and a micrometer-scale path length that induce clustered, difficult-to-repair DNA damage. In the multicenter retrospective WARMTH Act study of 488 heavily pretreated patients, actinium-225-PSMA therapy yielded a median overall survival of 15.5 months and progression-free survival of 7.9 months, though xerostomia emerged in 68 percent of evaluable patients after the first cycle. The Vienna reviewers position actinium-225 not as a stronger version of lutetium but as a distinct intensification strategy, best reserved for selected refractory scenarios while its dosimetry and sequencing with lutetium remain under active investigation.

Somatosatin receptor targeting, meanwhile, remains the model of stability in neuroendocrine tumors. Among the five SSTR subtypes, SSTR2 predominates in well-differentiated gastroenteropancreatic and midgut neuroendocrine tumors, providing the molecular basis for gallium-68-labeled DOTATATE, DOTATOC, and DOTANOC imaging and for lutetium-177-DOTATATE peptide receptor radionuclide therapy (PRRT), now a standard option for advanced SSTR-positive disease. European practice recommendations designate SSTR PET/CT as the reference-standard imaging modality for candidate selection, with FDG PET/CT complementing it in dedifferentiated or aggressive lesions. Perhaps the most intriguing recent development is the shift from agonists to antagonists. Because antagonists bind a broader range of receptor conformations and more binding sites, they can achieve higher lesion uptake and better tumor-to-background contrast, particularly in liver metastases, as confirmed by a 2025 systematic review and meta-analysis. The antagonist therapeutic lutetium-177-satoreotide tetraxetan has shown high tumor uptake and promising disease control in phase I/II testing, though hematologic toxicity and dosimetric challenges mean it remains an evolving complement rather than a replacement for agonist PRRT.

CXCR4 illustrates a fundamentally different clinical logic. This chemokine receptor drives tumor-cell migration, homing, and marrow invasion, and is associated with aggressiveness and poor prognosis in hematologic malignancies. Imaging with gallium-68-pentixafor PET is especially valuable in B-cell lymphomas and multiple myeloma, sometimes offering higher lesion contrast than FDG PET, and a prospective study in primary central nervous system lymphoma found that a fluorine-18-labeled CXCR4 tracer identified more lesions than FDG PET/CT. Therapy, using lutetium-177 or yttrium-90-labeled pentixather, has deliberately bypassed broad application and instead concentrated on high-intensity bridging or myeloablative treatment before hematopoietic stem-cell transplantation in heavily pretreated lymphoma and myeloma. The marrow toxicity in this setting is not merely an adverse event but part of the therapeutic concept, demanding close coordination between nuclear medicine, hematology, and transplant teams.

FAP targeting extends theranostics beyond tumor cells to the tumor microenvironment itself. FAP is a type II transmembrane serine protease overexpressed on cancer-associated fibroblasts but largely silent in normal adult tissue, making FAPI imaging remarkably effective across stromal-rich solid tumors including pancreatic, biliary, gastrointestinal, and ovarian cancers, sarcomas, and peritoneal metastases. Therapy, however, has lagged imaging for a fundamental pharmacologic reason: early small-molecule FAPI tracers clear rapidly, which produces pristine PET images but limits tumor retention and absorbed dose when labeled with lutetium-177. A 2025 phase II study of lutetium-177-LNC1004 achieved a disease control rate of 46 percent in 28 end-stage metastatic patients with high FAP expression, and a prospective study of the peptide ligand FAP-2286 showed feasibility and safety in FAP-positive gastrointestinal tumors, though benefit was mostly disease stabilization. The competitive frontier now lies in ligand engineering—Evans blue conjugation, albumin-binding modifications, dimerization, and novel scaffolds—all aimed at prolonging intratumoral retention to match the physical half-life of the radionuclide.

Across all four systems, the review identifies recurring translational bottlenecks. Target heterogeneity, both between patients and among lesions within the same patient, can evolve under treatment pressure, as seen when prostate tumors undergo neuroendocrine transdifferentiation and lose PSMA expression. Individualized dosimetry has become clinically decisive rather than academic: patient-specific studies reveal substantial interpatient variation in renal, salivary, lacrimal, and marrow radiation burden even under identical dosing, and the 2025 DUONEN trial showed that per-cycle organ dosimetry can safely guide activity adjustments below cumulative thresholds of 23 Gy for kidneys and 2 Gy for bone marrow. Organ protection is shifting from passive management toward active optimization through ligand design and dosimetry-guided dosing, particularly for the salivary glands that limit alpha-emitter PSMA therapy.

The wider horizon is expanding on two axes simultaneously. New targets including CCK2R, GRPR, and CAIX are entering clinical development, while novel radionuclides such as lead-212, terbium-161, and copper- and lead-based theranostic pairs offer different half-lives, emission profiles, and tissue ranges that change which ligands and lesion types they suit. The first-in-human VIOLET study of terbium-161-PSMA-I&T in metastatic castration-resistant prostate cancer exemplifies this dual expansion within an established target system. The Vienna authors argue that radioligand therapy must ultimately be embedded in multidisciplinary pathways that weigh sequencing against androgen receptor inhibitors, chemotherapy, PARP inhibitors, and immunotherapy, and that integrate supportive care, symptom control, and quality-of-life assessment rather than relying solely on imaging or biochemical endpoints. Their verdict is measured but clear: PSMA and SSTR constitute the proven backbone of nuclear theranostics, while CXCR4 and FAPI point toward a future in which the tumor microenvironment and the marrow niche, not just the tumor cell, become therapeutic targets in their own right.

Subject of Research: Molecular targets in oncologic radionuclide therapy and theranostics

Article Title: Advances in molecular targets for oncologic radionuclide therapy

Article References: Zhang, H., Xue, S., Wen, S., Wang, Z., Li, X., Jia, Y., Hacker, M., & Li, X. (2026). Advances in molecular targets for oncologic radionuclide therapy. Holistic Integrative Oncology, 5(1), Article 77. https://doi.org/10.1007/s44178-026-00293-6

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00293-6

Keywords: radionuclide therapy, theranostics, PSMA, SSTR, CXCR4, FAPI, lutetium-177, actinium-225, dosimetry, prostate cancer, neuroendocrine tumors, radioligand therapy

The rationale behind the approach rests on a striking biological quirk. Although prostate-specific membrane antigen, or PSMA, takes its name from the prostate, it is also expressed on the neovasculature of many solid tumors, including glioblastoma. The rapidly growing blood vessels that feed these tumors display the protein at high density, while normal brain vasculature largely does not. This creates a therapeutic window: a radioligand that homes in on PSMA can deliver cytotoxic radiation to the tumor’s own blood supply, starving it from within while sparing healthy tissue. Previous work by Wernicke and colleagues established PSMA as a vascular target in glioblastoma, and multicenter imaging studies have since confirmed that PSMA-targeted PET tracers accumulate in a substantial proportion of high-grade gliomas, making the antigen both an imaging biomarker and a candidate therapeutic target.

Actinium-225 is among the most potent radionuclides available to nuclear medicine. It decays through a cascade of four alpha emissions, each depositing enormous energy over distances of only a few cell diameters. This dense, short-range radiation causes clusters of irreparable double-strand DNA breaks, killing targeted cells and even neighboring tumor cells through a bystander effect, regardless of oxygenation or cell-cycle status, factors that often blunt the effectiveness of conventional photon radiotherapy. The same short particle range, however, demands that the radionuclide be delivered with precision, which is precisely what the PSMA-targeting ligand is designed to achieve. In prostate cancer, [²²⁵Ac]-PSMA-617 has produced dramatic responses, but extending this technology to brain tumors required evidence that the ligand would actually localize to glioma tissue in patients.

To test the concept, the researchers treated four patients with histologically confirmed recurrent high-grade glioma: three with glioblastoma and one with a WHO grade III high-grade diffuse glial tumor. Each patient received [²²⁵Ac]-PSMA intravenously at a dose of 100 kilobecquerels per kilogram of body weight per cycle, with treatment cycles intended at intervals of eight to twelve weeks. Before therapy, all patients underwent PSMA-targeted PET imaging with either [⁶⁸Ga]-PSMA PET/MRI or PET/CT, combined with contrast-enhanced magnetic resonance imaging, to identify PSMA-avid index lesions. Baseline and follow-up assessments were performed visually and then quantified using semi-quantitative parameters on the hybrid imaging studies, while clinical status and hematologic parameters were monitored throughout therapy and follow-up.

The imaging results offered cautious grounds for optimism. Although every patient ultimately developed progressive disease, the predefined PSMA-avid index lesion regressed in one patient and remained stable in another. In a disease where progression is typically rapid and relentless, any evidence of local disease control is noteworthy, particularly with a first-in-kind systemic therapy delivered on an outpatient basis. The investigators emphasize that the study was designed to assess feasibility, safety, and preliminary efficacy rather than survival outcomes, and the small cohort of four patients means that no firm conclusions about efficacy can yet be drawn. Nevertheless, the observation that a radiopharmaceutical could produce measurable tumor control in heavily pretreated brain tumor patients represents a proof of principle for the entire strategy.

Safety findings were equally encouraging. No grade three or higher adverse events attributable to [²²⁵Ac]-PSMA were observed, and there were no treatment-related deaths. The toxicity that did occur was limited and low-grade, consisting mainly of mild xerostomia, or dry mouth, a well-known consequence of PSMA-targeted radioligand therapy caused by PSMA expression in the salivary glands. This favorable tolerability profile is significant because patients with recurrent glioma have often already endured intensive radiation and chemotherapy, leaving limited reserve for additional myelosuppressive treatment. The absence of hematologic toxicity in this small series suggests that the 100 kBq/kg dose level can be delivered safely, though the authors caution that larger cohorts are needed to characterize the full toxicity profile.

The theranostic framework underlying the trial deserves particular attention. Theranostics pairs a diagnostic imaging agent with a therapeutic compound sharing the same molecular target, allowing clinicians to confirm target expression before committing a patient to treatment. In this study, [⁶⁸Ga]-PSMA PET served as the companion diagnostic, identifying which lesions expressed PSMA on their vasculature and would therefore be expected to accumulate the alpha-emitting therapeutic. This personalized selection process, now standard in prostate cancer radioligand therapy following the success of lutetium-177 PSMA-617, could in principle spare glioma patients from ineffective treatment while concentrating clinical trials on the subset of tumors most likely to respond.

Significant hurdles remain before this approach can move toward routine clinical use. Alpha-emitting radiopharmaceuticals pose unique challenges, including the global scarcity of actinium-225, which is produced in limited quantities at only a handful of accelerator facilities worldwide, a constraint documented in recent mapping studies of global alpha-emitter production. The decay daughters of actinium-225 can also break free from their chelator and redistribute to normal organs, particularly the kidneys and salivary glands, a phenomenon that preclinical dosimetry studies are actively working to quantify and mitigate. Delivery to brain tumors is further complicated by the blood-brain barrier, although the vascular targeting strategy may partially circumvent this obstacle because the tumor neovasculature lies on the accessible side of the barrier. Optimal dose, cycle number, and combination with other therapies all remain to be defined.

Earlier targeted alpha therapy studies in glioma, including trials of actinium-225 and bismuth-213 labeled substance P analogues delivered directly into resection cavities, have demonstrated that alpha radiation can achieve long-term tumor control in selected patients, and reports of durable responses in low-grade gliomas have fueled interest in expanding these approaches. The present study extends the concept to systemic administration, which is far simpler logistically and could theoretically address both the primary lesion and distant tumor satellites. The Istanbul team, which received no external funding for the work and declared no competing interests, conducted the study with institutional ethics approval and informed consent from all participants, in accordance with the Declaration of Helsinki.

For now, the message from this pilot experience is one of measured hope. Systemic [²²⁵Ac]-PSMA therapy appeared feasible and well tolerated in patients who had exhausted conventional options, and it produced preliminary evidence of disease control in PSMA-expressing recurrent high-grade glioma. The authors and observers of the field alike stress that these findings must be validated in larger, controlled studies with longer follow-up before any claims of clinical benefit can be made. Yet the convergence of several trends, including expanding global production of actinium-225, improving PSMA PET imaging of brain tumors, and growing clinical experience with alpha radioligand therapy, suggests that targeted alpha therapy may be poised to become a genuine new frontier in the treatment of one of medicine’s most lethal cancers. If subsequent trials confirm and extend these early signals, the theranostic pairing of PSMA imaging with alpha-emitting therapy could offer patients with recurrent glioma something they have rarely had: a precisely targeted, systemically deliverable option with real potential to alter the course of their disease.

Subject of Research: Systemic targeted alpha therapy using actinium-225 labeled PSMA radioligand for recurrent high-grade glioma

Article Title: Targeted alpha therapy for recurrent high-grade glioma with [²²⁵Ac]-PSMA: a new theranostic approach

Article References: Sayman, H. B., Aras, O., Hekim, M. V., Sağlam, K., Akgün, E., & Dinçbaş, F. Ö. (2026). Targeted alpha therapy for recurrent high-grade glioma with [²²⁵Ac]-PSMA: a new theranostic approach. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08194-6

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08194-6

Keywords: glioblastoma, high-grade glioma, targeted alpha therapy, actinium-225, PSMA, theranostics, radioligand therapy, PET imaging, recurrent brain tumor, nuclear medicine, alpha emitters, PSMA-targeted therapy