Radioligand therapy has transformed the treatment landscape for metastatic castration-resistant prostate cancer, or mCRPC, a stage of disease in which tumors no longer respond to hormone deprivation. The approved therapy, lutetium-177 labeled PSMA-617, homes in on prostate-specific membrane antigen, a molecule abundantly displayed on the surface of prostate cancer cells, and delivers beta radiation directly to metastatic deposits. Clinical trials demonstrated improved survival and tolerability, leading to regulatory approval in both Europe and the United States. Yet not every patient responds, and resistance eventually emerges in many. This therapeutic gap has driven a search for alternative radionuclides capable of packing more lethal energy into tumor cells, and terbium-161 has quickly become one of the most compelling candidates.

The appeal of terbium-161 lies in its distinctive decay physics. It closely mimics lutetium-177 in the ways that matter for clinical logistics: nearly identical half-lives of 6.9 versus 6.6 days, similar mean beta particle energies of 154 versus 133 kiloelectronvolts, and gamma emissions suitable for post-treatment imaging and dosimetry. But terbium-161 also emits a far greater abundance of conversion electrons and low-energy Auger electrons. These particles travel less than 500 nanometers in tissue and deposit energy at a high linear energy transfer of 4 to 26 kiloelectronvolts per micrometer. In principle, this means intense, highly localized irradiation precisely where the radioligand binds, particularly damaging for microscopic tumor deposits and single tumor cells that beta particles from lutetium-177 may spare. Preclinical studies and simulation work have consistently suggested a dosimetric advantage for terbium-161, and an initial head-to-head comparison in six patients corroborated the theory.

What has been missing is rigorous dosimetry in a larger patient cohort. The new study addresses that gap by analyzing 15 men with mCRPC enrolled in a prospective therapeutic registry who received terbium-161 labeled PSMA-617, typically as a second-line radioligand option after prior therapy with lutetium-177 or actinium-225. Patients received a median of two treatment cycles with a mean administered activity of 6.0 plus or minus 1.3 gigabecquerels per cycle, for a cumulative mean activity of 12.3 plus or minus 4.6 gigabecquerels. The radiolabeling process, adapted from established lutetium-177 methodology, achieved radiochemical yields and purity consistently above 99 percent, and administered activities were individually tailored to each patient’s tumor burden, renal function, and blood counts.

Dosimetric assessment relied on a hybrid two-dimensional and three-dimensional imaging protocol. Planar whole-body scans were acquired at roughly 24, 48, and at least 69 hours after injection, supplemented by SPECT/CT imaging of the head and neck on day one and of the abdomen on day two. Using a 74.6 kiloelectronvolt photopeak window, scatter and attenuation corrections, partial-volume corrections derived from terbium-161 phantom measurements, and automated Bayesian volume segmentation, the physics team calculated absorbed doses with the OLINDA/EXM software following the internationally recognized MIRD schema. This combination of planar kinetics rescaled by quantitative SPECT values represents a methodologically sound middle ground between speed and accuracy, and it allowed the researchers to track 43 individual metastatic lesions alongside the kidneys, liver, parotid glands, and submandibular glands.

The organ dosimetry results place terbium-161 therapy squarely within the safety envelope established for lutetium-177. Kidneys received the highest mean absorbed dose at 0.70 plus or minus 0.41 gray per gigabecquerel, followed by the parotid glands at 0.40 plus or minus 0.20 and the submandibular glands at 0.36 plus or minus 0.14 gray per gigabecquerel, with the liver absorbing the least at 0.13 plus or minus 0.08 gray per gigabecquerel. Absorbed doses did not change significantly between the first and second treatment cycles, and no deterioration in renal toxicity was observed even in the two patients with the highest kidney doses, both of whom entered the study with pre-existing renal risk factors. The reported kidney dose range overlaps the published spectrum for lutetium-177 PSMA-617, which spans roughly 0.39 to 0.99 gray per gigabecquerel across major studies.

The tumor findings are where the therapy’s promise becomes most visible. Across 43 analyzed metastases, predominantly bone lesions, the mean absorbed tumor dose was 5.95 plus or minus 3.60 gray per gigabecquerel, with individual lesions ranging from 0.68 to 32.34 gray per gigabecquerel. Bone metastases absorbed 5.89 plus or minus 4.20 gray per gigabecquerel and lymph node metastases 5.46 plus or minus 2.97 gray per gigabecquerel, with lesions retaining the tracer for a mean effective half-life of 44 hours. These figures compare favorably with meta-analytic data for lutetium-177 PSMA ligands, which reported mean bone lesion doses of about 3.6 to 4.1 gray per gigabecquerel and soft-tissue doses of about 2.9 to 4.2 gray per gigabecquerel. Translated into therapeutic indices, the tumor-to-kidney ratio reached 10.55 plus or minus 8.32 and the tumor-to-parotid ratio 16.15 plus or minus 11.85, well above the kidney therapeutic indices of 3.6 to 5.3 previously published for lutetium-177-based approaches.

The study also probed the relationship between dose and response, finding a suggestive but statistically non-significant trend. Patients whose disease progressed biochemically tended to have received lower tumor absorbed doses, averaging 3.15 plus or minus 1.62 gray per gigabecquerel, than patients with stable disease at 5.81 plus or minus 2.64 or partial PSA remission at 6.52 plus or minus 3.27 gray per gigabecquerel, with a moderate correlation between tumor dose and PSA change. The authors attribute the lack of statistical significance to the small, heterogeneous, and heavily pretreated cohort rather than to any absence of a dose-response relationship, which earlier work in PSMA radioligand therapy has supported. Importantly, no severe adverse events or treatment discontinuations occurred in the cohort, reinforcing the emerging picture from the independent VIOLET phase 1/2 trial of terbium-161 PSMA-I&T that this radionuclide is safe and clinically active.

The investigators are careful to note the limitations: the cohort was small, all patients had undergone multiple prior radioligand therapy cycles that may have altered tracer kinetics, red marrow dosimetry was not feasible, and lesion selection was constrained by imaging criteria that could introduce bias. Nonetheless, as the largest terbium-161 PSMA dosimetry study published to date, the work provides a quantitative foundation for a therapy that could ultimately serve not only prostate cancer patients but also those receiving peptide receptor radionuclide therapy or FAP-targeted treatments. The favorable tumor-to-organ ratios reported here support continued clinical development, and the authors argue that individualized dosimetry will be central to future treatment planning, allowing clinicians to adapt activity prescriptions per patient to maximize tumor kill while protecting kidneys and salivary glands. Larger prospective trials will determine whether terbium-161’s physical advantages translate into a survival benefit, but the dosimetric arithmetic now clearly favors it.

Subject of Research: Organ and tumor dosimetry of terbium-161 PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer

Article Title: Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC

Article References: Schaefer-Schuler, A., Blickle, A., Ganz, S., Petto, S., Burgard, C., Speicher, T., Bastian, M. B., Maus, S., Bartholomä, M., Ezziddin, S., & Rosar, F. (2026). Organ and tumor dosimetry of [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08171-z

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08171-z

Keywords: terbium-161, PSMA-617, radioligand therapy, dosimetry, prostate cancer, mCRPC, Auger electrons, SPECT/CT, tumor-to-organ ratio, nuclear medicine, theranostics, kidney dose

The study, published in the European Journal of Nuclear Medicine and Molecular Imaging, was motivated by a stubborn clinical problem. Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have transformed the treatment of melanoma and lung cancer, producing durable responses and long-term survival in subsets of patients. Prostate cancer, however, has largely resisted this revolution. Only small fractions of men with mCRPC benefit from agents such as pembrolizumab or nivolumab, a failure attributed to the disease’s low tumor mutational burden and its profoundly immunosuppressive microenvironment. Prostate tumors are, in immunological terms, cold: they present few recognizable targets to T cells and actively suppress the immune cells that do infiltrate them.

Radiation has long been proposed as a way to heat those cold tumors up. External beam radiotherapy can damage cancer cells in ways that release tumor antigens, trigger inflammatory cytokine secretion, recruit dendritic cells, and activate anti-tumor T cells. In rare, striking cases, irradiating one tumor site has even shrunk untreated lesions elsewhere in the body, the so-called abscopal effect. Clinical trials combining radiation with checkpoint inhibitors have shown hints of enhanced activity in genitourinary cancers. Radium-223, an intravenously administered alpha emitter approved for mCRPC patients with predominantly bone metastases, seemed like an elegant systemic version of this strategy. In the pivotal phase III ALSYMPCA trial it extended overall survival by 3.6 months, and because it circulates through the bloodstream it can in principle irradiate every bone lesion at once.

Earlier laboratory work had fed optimism. In vitro experiments showed that sublethal exposure to radium-223 enhanced the ability of cytotoxic T lymphocytes to kill prostate cancer cells by inducing MHC class I and calreticulin, proteins central to antigen presentation. Studies of patient blood revealed that radium-223 enriched DNA damage repair pathways in plasma exosomes and raised exosomal levels of PD-L1, LAG-3 and IDO, immune checkpoints associated with immunosuppression and poorer survival. A mouse model of prostate cancer even suggested that combining radium-223 with anti-PD-1 and anti-CTLA-4 antibodies produced greater tumor regression than either immunotherapy alone. The clinical rationale for combining the radionuclide with checkpoint blockade appeared, on the surface, compelling.

To test that rationale rigorously in humans, the research team designed a biomarker discovery study in which patients received up to six injections of radium-223 at four-week intervals, while undergoing an unusually demanding battery of measurements. The centerpiece was sequential PET imaging with zirconium-89 labeled atezolizumab, a radiolabeled version of the approved PD-L1 antibody atezolizumab. Produced under Good Manufacturing Practice at the University Medical Center Groningen and injected at a tracer dose of 37 MBq, roughly 11 milligrams of antibody and less than one percent of a therapeutic dose, the tracer allowed the team to quantify whole-body PD-L1 expression in vivo, something a single biopsy can never do. Gallium-68 PSMA PET/CT served as the anatomical and molecular reference, pinpointing viable prostate cancer lesions in the skeleton against which atezolizumab uptake could be measured.

The imaging results were striking. At baseline, uptake of the PD-L1 tracer in PSMA-positive bone metastases was low overall and highly heterogeneous, both between patients and between individual lesions within the same patient, with a median standardized uptake value of 2.5 across the total volume of PSMA-positive bone disease. After three cycles of radium-223, that median fell to 0.9, a statistically significant median decrease of 33 percent, while PSMA uptake in the same lesions remained essentially stable. Crucially, the decline was independent of whether a patient’s disease responded on PSMA PET: good responders, defined as those remaining on radium-223 for at least 24 weeks, and poor responders showed comparable drops. Some lesions even lost PD-L1 signal while their PSMA signal held steady, and new PSMA-avid disease appearing at the borders of treated lesions showed lower tracer uptake than the original metastases had at baseline.

Tissue analysis told a consistent story. Guided by PSMA PET, the team obtained bone metastasis biopsies at baseline in 25 patients, with tumor cells present in 76 percent of samples. Multiplex immunohistochemistry revealed low PD-L1 expression, found mainly on tumor cells but also on non-tumor cells, mirroring the modest and variable PET signal. In the small number of patients who provided sequential biopsies, the number of lymphocytes in both tumor tissue and surrounding bone marrow decreased after three cycles of radium-223, and one on-treatment biopsy showed necrosis consistent with radiation effect. Flow cytometry of blood samples reinforced the picture: circulating lymphocyte counts fell during therapy, and good responders showed a significant rise in TIM3-positive T cells, a marker of T cell exhaustion, after treatment.

The authors argue that the drop in atezolizumab uptake most likely reflects a treatment-induced loss of immune cells within the tumor microenvironment, and possibly a reduction in PD-L1 expression per cell, rather than simply fewer tumor cells. Because PSMA uptake did not fall in parallel, and because new PSMA-positive disease did not carry elevated PD-L1 signal, the immune compartment appears to be the dominant source of the tracer signal and the main casualty of the alpha radiation. The team acknowledges limitations, including the possibility of confounding by changes in tumor vascularization or receptor saturation, though the stability of tracer uptake in bone marrow and cortex over time supports a genuine treatment effect. Sequential biopsies were feasible in only a handful of patients, and decalcification of bone samples may have masked PD-L1 staining with standard clinical antibodies.

The clinical implications are sobering but clarifying. The findings align with the disappointing results of phase Ib and phase II trials that added radium-223 to atezolizumab, pembrolizumab or enzalutamide and found no benefit for mCRPC patients. Far from sensitizing prostate cancer to PD-L1 blockade, alpha radiation appears to thin out the very immune cells that checkpoint inhibitors rely upon, potentially undermining immunogenic effects of irradiation through sheer depletion of the lymphocyte pool. The researchers suggest that future combination strategies might instead turn to radionuclides with lower linear energy transfer delivered at lower doses, such as lutetium-177 PSMA-targeted therapy, which could induce immunogenic signaling without devastating the immune infiltrate. For now, the study stands as a powerful demonstration of what whole-body immune PET can reveal: a molecular narrative of treatment response that biopsies alone could never tell, and a cautionary lesson about assuming that radiation and immunotherapy are natural allies in every tumor type.

Subject of Research: The effect of radium-223 alpha radiation on PD-L1 expression and the immune microenvironment of bone metastases in metastatic castration-resistant prostate cancer, measured with zirconium-89 atezolizumab PET imaging and immunohistochemistry.

Article Title: Radium-223 decreases PD-L1 expression in bone metastases: A study with [89Zr]Zr-atezolizumab PET and immunohistological correlation

Article References: Ling, S. W., de Jong, A., Gorris, M., Segbers, M., Graven, L., van Driel, M., van Leenders, G., Isebia, K., de Hooge, M. L., Hamberg, P., Mehra, N., van Brakel, M., de Wit, R., Debets, R., de Vries, E., Brabander, T., de Vries, J., & van der Veldt, A. (2026). Radium-223 decreases PD-L1 expression in bone metastases: A study with [89Zr]Zr-atezolizumab PET and immunohistological correlation. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08175-9

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08175-9

Keywords: radium-223, prostate cancer, PD-L1, atezolizumab, PET imaging, bone metastases, immune checkpoint inhibitors, PSMA, immunotherapy, alpha radiation, tumor microenvironment, mCRPC