The research combined a multicenter contouring exercise with a retrospective recurrence-mapping analysis. Ten radiation oncologists from eight centers independently delineated the prostate-bed CTV in one postoperative case. Agreement was summarized using the Dice similarity coefficient, or DSC, and the 95th-percentile Hausdorff distance, or HD95. The mean pairwise DSC was 0.767 ± 0.046, and the mean HD95 was 8.244 ± 2.347 mm. The investigators reported considerable interobserver variation, particularly around the bladder. Because the exercise involved a single postoperative case, the measurements characterize agreement for that case rather than the full anatomical and clinical variation encountered in routine practice.

For the recurrence analysis, the investigators assigned PSMA PET-positive prostate-bed lesions to an exploratory framework containing six anatomical zones. In addition to the bladder-neck and vesicourethral anastomotic regions, the retrovesical area, Zone 5b, contained 17 of 97 events, or 17.5%, and the dorsolateral perivesical region, Zone 5a, contained 12 events, or 12.4%. The cranial seminal-vesicle-bed region, Zone 6, contained seven events, while the ventral perivesical region, Zone 4, contained only two of 97 events, or 2.1%. The observed maximum extents were 1.3 cm for the 12 Zone 5a events and 3.0 cm for the seven Zone 6 events. These figures describe the extent of recurrence observed in this sample; they do not establish universally safe CTV boundaries or predict recurrence patterns in all patients after surgery.

The researchers also assessed whether recurrence centroids were covered by CTV definitions from the ESTRO-ACROP 2023, GFRU 2020, and RTOG 2010 guidelines. At the patient level, all identified recurrence centroids were covered in 54 of 63 patients by ESTRO-ACROP, or 85.7% (95% confidence interval, 75.0%–92.3%). Coverage was 52 of 63 patients, or 82.5% (95% confidence interval, 71.4%–90.0%), for GFRU and 53 of 63 patients, or 84.1% (95% confidence interval, 73.2%–91.1%), for RTOG. These results are centroid-based assessments and therefore do not demonstrate that every portion of every recurrence was contained within the corresponding CTVs.

Overall, the study found that PSMA PET-positive recurrences were unevenly distributed within the prostate bed after radical prostatectomy and that radiation oncologists showed notable variation when contouring postoperative targets. The low event count in the ventral perivesical region provides an imaging-based rationale for further evaluation of CTV boundaries in that area, while the contouring results underscore the variation around the bladder. The findings may help inform future studies of postoperative target-volume refinement, but the authors emphasized that validation in larger multicenter cohorts is required. The study did not test whether changing any guideline boundary would improve clinical outcomes, and the contouring exercise and retrospective recurrence analysis do not establish a causal effect of CTV size on recurrence or treatment success.

Subject of Research: Postoperative prostate-bed recurrence mapping and radiation target-volume delineation

Article Title: PSMA PET recurrence mapping and guideline coverage after radical prostatectomy: implications for postoperative prostate bed CTV delineation

Article References: Qi, X., Zhang, H., Chen, C., Wu, J., Liao, X., Zhang, J., He, L., Lu, N., Shen, Y., Wang, H., Zhong, Q., Li, Y., Zhang, M., Gao, X., & Li, H. (2026). PSMA PET recurrence mapping and guideline coverage after radical prostatectomy: implications for postoperative prostate bed CTV delineation. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02931-x

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02931-x

Keywords: PSMA PET, prostate cancer, radical prostatectomy, prostate bed, recurrence mapping, salvage radiotherapy, clinical target volume, radiation oncology, interobserver variation, guideline coverage, PSMA, recurrence

The clinical stakes are high because radiopharmaceutical therapy (RPT) is conceptually precise yet operationally crude. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for prostate cancer, somatostatin-receptor peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors, radioiodine therapy for thyroid cancer, and yttrium-90 radioembolization for liver tumors all embody the theranostic principle: image the target, treat the target, quantify the biodistribution, absorbed dose, and response. Yet despite this conceptual elegance, many workflows still administer fixed or empirically chosen activities, and the supporting physics — labor-intensive segmentation, serial imaging, activity quantification, time-activity modeling, and absorbed-dose reporting — remains slow and inconsistent across centers.

AI is attractive precisely because the RPT workflow is data-rich and quantitatively constrained. Patients undergo baseline PET/CT or SPECT/CT, post-therapy quantitative imaging, serial laboratory testing, symptom and toxicity monitoring, and repeated treatment cycles. These data can be linked to activity concentration, time-integrated activity, absorbed dose, effective half-life, tumor burden, and clinical measures of organ reserve. Learned models may reduce the segmentation burden, standardize tumor-burden quantification, infer kinetic parameters, approximate computationally expensive dose calculations, and estimate response or toxicity risk. The central clinical question, the authors argue, is not whether AI can produce a high-performing model in a retrospective dataset, but whether an AI-supported output can safely and reproducibly improve treatment decisions — whether to treat, whether to intensify or de-escalate activity, whether to delay or discontinue a cycle, whether the predicted organ dose is acceptable, and whether early response suggests continued benefit.

The mapped evidence set is revealing in its composition. Among the 73 full journal reports, 17 were PSMA-related, 16 addressed SSTR/PRRT, 15 radioiodine, 14 yttrium-90 radioembolization, and 11 were cross-platform or emerging-target studies. Sixteen addressed segmentation or quantitative tumor burden, 32 addressed selection, response, prognosis, toxicity, or safety and logistics, and 25 addressed registration, preprocessing, or dosimetry. But the validation picture is sobering: 51 reports were retrospective, only one was an explicitly prospective clinical or technical evaluation, nine were technical, synthetic, or phantom evaluations, and the temporal design was unclear or conflicting in 12. Only seven reported an external-type held-out evaluation, and just four clearly held out an entire institution. One report described explicit calibration, one propagated task-level uncertainty, and none evaluated a prospective AI-guided treatment policy.

The technical highlights are nonetheless substantial. Zhao and colleagues trained a deep neural network to detect and segment PSMA-avid lesions across 130 training patients and 63 patient-separated test patients, achieving F1 scores of 0.99 for bone lesions and 0.92 for lymph-node lesions. Perret and colleagues evaluated nnU-Net lesion segmentation on paired gallium-68 PSMA PET/CT and first-cycle lutetium-177 PSMA SPECT/CT in 73 patients, training at one center and testing at a second — a genuine held-out-center validation yielding external Dice scores of 0.76 to 0.77 for PET and 0.78 for PET-guided SPECT, though PET volume errors were highly unstable and activity or absorbed-dose consequences were never tested. In PRRT dosimetry, Nakaichi and colleagues reported that deep-learning segmentation cut the median total workflow time from 54.3 to 47.0 minutes, a modest but statistically significant acceleration — though the reference contour was the staff-corrected AI output itself, meaning the study validated supervised workflow support rather than autonomous segmentation.

Dosimetry — the quantitative heart of personalized RPT — shows both the promise and the peril. Mansouri and colleagues used a hybrid transformer model to predict lutetium-177 DOTATATE voxel dose maps against Monte Carlo references in 22 patients, reporting a voxel relative absolute error of 5.28 percent with patient-grouped cross-validation. Mansouri and colleagues also applied Swin UNETR deep learning to attenuation and scatter correction of technetium-99m MAA SPECT in 222 patients toward yttrium-90 radioembolization quantification, with a blind internal holdout showing voxel mean dose error of at most 0.003 Gy. Jalilifar and colleagues trained a multilayer perceptron to estimate patient-specific iodine-131 dosimetry from a single oblique planar view, with organ-specific differences from Monte Carlo reference ranging from −14.8 to +11.2 percent in a 23-patient external cohort. Georgiou and colleagues trained a feed-forward neural network to estimate the MIRD maximum permissible iodine-131 activity from reduced-time-point imaging, with a nonsignificant paired difference against full five-time-point calculations — but the authors stress that a nonsignificant difference does not establish equivalence without a prespecified clinical margin.

On the decision side, the picture is more cautious. In PSMA therapy, Pan and colleagues developed a dual-tracer radiomics nomogram to estimate PSMA-negative but FDG-positive disease — a biological mismatch that predicts radioligand therapy failure — achieving an AUC of 0.83 in development, with decision analysis suggesting a 5 percent threshold could avoid 21 percent of FDG PET/CT examinations while missing only 2 percent of mismatch cases. But a separate cohort tested only the prognostic associations, not the primary classification performance. In PRRT, Baur and colleagues used multimodal deep learning fusing PET/CT and laboratory variables to predict progression-free survival in 116 patients, achieving an AUC of 0.72 with repeated cross-validation — retrospective, single-center, internally validated evidence. In radioiodine therapy, Luo and colleagues used LightGBM with SHAP interpretability in 950 patients to predict non-excellent response, achieving a test AUC of 0.896 versus 0.842 for logistic regression — but because the model incorporated administered activity and post-therapy scan variables, it informs post-treatment response stratification rather than pretreatment selection. Popovic and colleagues trained an artificial neural network to imitate an experienced physician’s radioiodine activity recommendations, achieving 95.71 percent test accuracy and weighted kappa of 0.96 — expert-decision imitation, not outcome or treatment-benefit validation.

The authors organize these gaps into an eight-domain evidence-to-decision synthesis covering quantitative fidelity, reference-standard appropriateness, external or prospective validation, clinical-endpoint relevance, dose-response or dose-toxicity linkage, workflow and human oversight, uncertainty and quality assurance, and decision impact. This is explicitly a narrative organizing aid, not a validated score or adoption standard. The domains were derived by mapping recurrent gaps across the retained evidence and comparing them with established reporting frameworks including RELAINCE, RQS 2.0, CLAIM, TRIPOD+AI, PROBAST+AI, and DECIDE-AI. The RPT-specific emphasis is the separation of dosimetric fidelity, biological linkage, and treatment action — three things that are often conflated in the literature but must be established independently before any AI output can justify modifying a prescription.

Four inferential targets recur throughout the review, and distinguishing them is essential. Prognostic models estimate risk under observed care; response models estimate an endpoint after treatment; treatment-effect models estimate outcomes under specified alternatives; and treatment policies map patient states to actions. Only the latter two can directly justify choosing or withholding treatment. The authors note that target trial emulation, causal machine learning, and individualized treatment-effect estimation remain hypothesis-generating unless timing, eligibility, confounding, positivity, censoring, overlap, calibration, and decision impact are addressed — and even then they require prospective evaluation of a prespecified management rule. Dataset limitations compound the problem: lesion-level random splits can leak correlated observations across training and testing when multiple lesions arise from one patient, and reused or overlapping institutional cohorts can make apparently independent studies less independent than their citations suggest.

The research roadmap that emerges is pragmatic. The highest-yield infrastructure goal is a curated multicenter dataset linking diagnostic imaging, post-therapy quantitative imaging, laboratory values, administered activity, absorbed-dose estimates, response and toxicity endpoints, and longitudinal outcomes — with shared acquisition, reconstruction, calibration, segmentation, and dosimetry metadata so models can be compared under common rules. Multicenter dose-response consortia should pool patient-, organ-, lesion-, and voxel-level dosimetry with standardized clinical outcomes. Future trials should test prespecified adaptive strategies — response-adapted continuation or discontinuation, toxicity-aware delay, activity escalation or de-escalation — only when target expression, organ reserve, uncertainty bounds, and protocol-defined safety constraints support these actions. The near-term opportunity, the authors conclude, is human-supervised decision support rather than fully autonomous adaptation: a useful system should display its inputs, uncertainty, reference standards, validation settings, and proposed clinical actions, and flag cases outside its development domain. Treatment-changing use will require standardized quantitative imaging, appropriate dosimetry comparators, multicenter and prospective validation, calibrated uncertainty, clinically established dose-response or dose-toxicity relationships, and a prespecified evaluation of decision impact — a demanding but achievable sequence that would finally convert technical feasibility into clinical benefit.

Subject of Research: Artificial intelligence in oncologic theranostics and radiopharmaceutical therapy

Article Title: Artificial intelligence across oncologic theranostics: evidence for patient stratification, dosimetry, and adaptive radiopharmaceutical therapy

Article References: Banala, M., Ezuddin, S., Foley, M., & Kuker, R. (2026). Artificial intelligence across oncologic theranostics: evidence for patient stratification, dosimetry, and adaptive radiopharmaceutical therapy. Frontiers in Nuclear Medicine, 6, Article 1935247. https://doi.org/10.3389/fnume.2026.1935247

Image Credits: AI Generated

DOI: 10.3389/fnume.2026.1935247

Keywords: artificial intelligence, radiopharmaceutical therapy, theranostics, dosimetry, PSMA, PRRT, radioiodine therapy, nuclear medicine, machine learning, cancer treatment, Artificial, intelligence

Among the most technically striking reports is a paired imaging and treatment approach for prostate cancer built on compounds that target PSMA, or prostate-specific membrane antigen, a protein abundantly expressed on prostate cancer cells. The strategy pairs a diagnostic imaging agent with a therapeutic compound designed to bind the same molecular target, an approach at the heart of theranostics, the practice of using matched agents to first visualize a disease target and then deliver radiation to it. In mouse models, the therapeutic agent accumulated in tumors at 2.2 to 3.5 times higher levels than a reference treatment, while producing similar effects on tumor growth. Just as importantly, the imaging agent showed a distribution pattern closely matching that of the therapeutic compound, suggesting it could serve as a reliable preview of where the therapy would travel in the body. That pairing is precisely the logic that makes theranostics attractive: if the diagnostic tracer lights up a tumor, the therapeutic counterpart should follow the same path.

A second study tackled one of the persistent frustrations of molecular imaging: background noise from radioactive material still circulating in the bloodstream. When unbound tracer lingers in the blood, it can wash out the contrast between tumor and surrounding tissue, making small or subtle lesions harder to see. The researchers developed a method that uses enzymes to clear unneeded radioactive material from the circulation after injection. In mice, treatment with the enzyme carboxypeptidase G2 increased the imaging signal from tumors relative to blood by more than 40 percent. The concept relies on a clever chemical design in which the tracer is engineered so that the enzyme can alter it in the blood, accelerating its clearance, while the tracer that has already bound to its cancer target remains intact. The result is a cleaner image in which the tumor stands out more clearly against a quieter background, potentially helping clinicians visualize cancer targets that would otherwise be lost in vascular noise.

Breast cancer imaging also featured prominently in the new releases. Researchers evaluated a new PET tracer that targets nectin-4, a protein found in several cancers, in a pilot study of six patients with breast cancer. The tracer performed similarly to standard imaging for primary tumors and most lymph node metastases, but in some patients it detected more bone and liver metastases than conventional approaches. Because nectin-4 is a recognized target for antibody-drug conjugates in oncology, a PET tracer that maps its expression could eventually help clinicians identify which patients are candidates for such therapies and monitor how the target behaves across different metastatic sites. The pilot study is small, and the authors’ findings will need validation in larger cohorts, but the pattern of detecting additional bone and liver lesions hints at biological information that current standard imaging may miss.

The brain was the focus of another new tracer evaluation, this one designed to detect erythropoietin receptors, which are involved in cellular responses to low oxygen levels. In two animal models of ischemic stroke, the tracer accumulated in damaged brain regions, mapping the territory where tissue is under metabolic stress. Tests of human stroke tissue also showed tracer binding, particularly in areas surrounding the most severely damaged tissue, a distribution known as the penumbra, where cells are endangered but not yet dead. A tracer that can visualize this stressed-but-salvageable tissue in living patients could become a valuable complement to existing stroke imaging, which primarily distinguishes between tissue that is already infarcted and tissue that is perfused. By revealing the molecular signature of hypoxic stress, the tracer could help clinicians and researchers better understand the time course of injury and, potentially, refine patient selection for reperfusion therapies.

Diabetes research took a different imaging angle, using PET/CT to measure insulin-producing beta cells in 26 people with type 1 diabetes. Those diagnosed less than seven years earlier had greater beta-cell mass, larger pancreases, and less pancreatic fat than those living with longer-duration disease. The study also found that beta-cell mass was associated with insulin-producing function, linking what the scanner sees to what the pancreas can still do. The findings carry implications for the design of clinical trials aimed at preserving or regenerating beta cells, since a noninvasive measure of beta-cell mass could serve as an endpoint or a stratification tool. They also add to a growing body of evidence that the pancreas itself changes in type 1 diabetes over time, not only in its endocrine cells but in its overall size and fat content.

Not all of the new work involved new chemistry. A survey of 227 patients undergoing PET/CT examined how people weigh scan quality, duration, comfort, and access when choosing among imaging options. Nearly eight in 10 respondents preferred better-quality images even if the scans took longer, and 80 percent said they were willing to wait more than an hour after tracer injection to obtain them. Most participants reported little or no discomfort during scanning. In an era when imaging protocols are often optimized for scanner throughput, the survey is a reminder that patients themselves frequently prioritize diagnostic confidence over convenience, and that longer acquisition times or longer waits between injection and imaging may be far more acceptable to patients than imaging departments assume.

Pediatric oncology and endocrine imaging each gained a practical refinement. In a study of five children ages 3 to 7 with advanced neuroblastoma, researchers evaluated a new PET tracer targeting somatostatin receptors. The imaging identified 17 cancer lesions with strong contrast between tumors and surrounding tissues, and the scan delivered a low overall radiation dose, an especially important consideration in young children. The results support further evaluation of the approach in pediatric patients, where minimizing radiation exposure while maximizing diagnostic yield is a central design constraint. Separately, a study of 119 patients with primary hyperparathyroidism found that delayed PET/CT imaging performed 60 minutes after injection improved image contrast compared with scans taken at 10 minutes. The delayed protocol changed clinical interpretation in 19.3 percent of cases and revealed a parathyroid adenoma in eight patients whose early scans had been negative, suggesting that simply waiting longer before imaging can meaningfully improve the detection of overactive parathyroid glands.

Finally, the collection included long-view safety data on radiopharmaceutical therapy for advanced prostate cancer. Researchers compared kidney function in patients treated with radiopharmaceutical therapy or chemotherapy and found that kidney function declined similarly in both groups during the first six months. Over longer follow-up, however, the picture diverged by baseline status: declines were more pronounced in patients with preexisting chronic kidney disease, while those with initially preserved kidney function showed no significant change. That distinction matters for clinicians weighing radioligand therapy for patients whose kidneys are already compromised, and it underscores the value of extended follow-up in understanding the durability of organ safety after targeted radiation treatment. Taken together, the nine studies sketch a field that is maturing on multiple fronts at once, refining the chemistry of tracers, the timing of scans, the interpretation of images, and the measurement of long-term consequences, all in service of imaging and treating disease at the level of individual molecules and individual patients.

Subject of Research: Advances in nuclear medicine and molecular imaging reported in The Journal of Nuclear Medicine

Article Title: The Journal of Nuclear Medicine ahead-of-print tip sheet: October 9, 2026

Article References: The Journal of Nuclear Medicine ahead-of-print tip sheet: October 9, 2026. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: nuclear medicine, PET, theranostics, prostate cancer, PSMA, breast cancer, nectin-4, ischemic stroke, type 1 diabetes, neuroblastoma, hyperparathyroidism, radiopharmaceutical therapy

Researchers at Fudan University Shanghai Cancer Center, writing in the journal Holistic Integrative Oncology, have assembled a comprehensive transcriptional landscape of prostate cancer progression by re-analyzing single-cell RNA sequencing data from 44 patient samples drawn from three prospective clinical trials. Their meta-cohort captured three clinically distinct stages of the disease: 13 samples of localized, treatment-naïve prostate cancer; 25 samples of hormone-sensitive prostate cancer obtained while patients were actively undergoing androgen deprivation therapy; and 6 samples of metastatic castration-resistant prostate cancer, collected from metastatic lesions in the prostate, lymph nodes, bladder, bone, and liver. The hormone-sensitive samples were particularly valuable, having been obtained 13 to 15 weeks after the initiation of a standardized ADT regimen, offering a snapshot of tumor cells in the act of adapting to therapeutic pressure rather than merely before or after it.

The technical challenge at the heart of the study was to reliably distinguish malignant epithelial cells from the benign cells that surround them within each tumor. The team applied a battery of quality-control filters, excluding cells with more than 25 percent mitochondrial gene expression, cells with fewer than 500 detected genes, and potential doublets exhibiting co-expression of incompatible lineage markers. Epithelial cells were identified by high expression of canonical markers such as EPCAM and KRT18, together with the absence of immune or stromal markers. The researchers then turned to inferCNVpy, a computational tool that infers single-cell copy number variation profiles by comparing each epithelial cell against a reference baseline built from 800 immune cells and 800 stromal cells. Clusters showing large-scale copy number aberrations consistent with genomic instability were classified as malignant, while those lacking such patterns were deemed normal. After these stringent steps, the final analytical dataset comprised 35,365 malignant tumor cells from 39 samples: 13 treatment-naïve, 22 hormone-sensitive, and 4 castration-resistant.

The first major finding concerns what happens inside tumor cells during the early months of ADT. Comparing malignant cells from hormone-sensitive samples with those from localized, untreated tumors, the researchers documented extensive transcriptional remodeling. Canonical androgen-responsive genes, including KLK3, the gene encoding the widely used clinical biomarker prostate-specific antigen, were significantly downregulated, confirming that the therapy was doing precisely what it was designed to do: suppressing androgen receptor signaling. Gene set enrichment analysis showed that the hallmark androgen response pathway was markedly suppressed in tumor cells under ADT, consistent with the known pharmacological effects of the treatment.

But the suppression of androgen signaling was only part of the story. In a finding with potentially far-reaching clinical implications, the team observed that ADT induced the activation of immune-associated transcriptional programs within the malignant cells themselves. Hallmark interferon-alpha and interferon-gamma response pathways were significantly enriched, alongside pathways involved in antigen processing and presentation. Over-representation analysis of the most upregulated genes in hormone-sensitive tumor cells further highlighted biological processes related to leukocyte differentiation, humoral immune response, and inflammatory signaling. In parallel, apoptosis-related pathways were significantly enriched, reflecting therapy-induced cellular stress and diminished survival signaling. Crucially, these immune programs were detected within the tumor cells themselves, independent of immune cell infiltration, indicating a direct transcriptional response of malignant cells to androgen deprivation rather than a secondary effect of a changing tumor microenvironment.

This observation aligns with a growing body of evidence suggesting that hormonal therapy can transiently enhance tumor immunogenicity. Prior work has shown that androgen receptor inhibition can increase the expression of major histocompatibility complex class I molecules on prostate cancer cells, potentially making them more visible to the immune system. The new single-cell data provide tumor-cell-intrinsic molecular support for this idea and carry an important practical implication: the timing of combination strategies that pair ADT with immune checkpoint inhibitors may matter enormously. If androgen deprivation opens a transient window of heightened immune visibility in tumor cells, then delivering immunotherapy during that window, rather than after resistance has fully established itself, could maximize therapeutic benefit. Clinical trials are already exploring this logic in metastatic castration-sensitive disease, and the new findings add molecular granularity to the rationale.

The second major finding shifts the focus to the endgame of the disease. When the researchers compared malignant cells from metastatic castration-resistant samples with those from localized, treatment-naïve tumors, they uncovered a strikingly different transcriptional profile, one dominated by genes involved in protein synthesis, mitochondrial function, and oncogenic signaling. Among the most prominently upregulated genes were ribosomal proteins such as RPL41 and RPSA, mitochondrial-encoded genes including MT-ND1 and MT-ND3, and FOLH1, the gene that encodes prostate-specific membrane antigen, or PSMA, a clinically important diagnostic and therapeutic target in advanced prostate cancer. These changes collectively point to an enhanced biosynthetic and metabolic capacity in castration-resistant tumor cells, a cellular state geared toward rapid growth under hostile conditions.

Pathway-level analysis crystallized this picture around a single dominant theme: MYC. Gene set enrichment analysis identified significant enrichment of MYC target gene sets in castration-resistant tumor cells, while androgen response pathways remained significantly downregulated relative to treatment-naïve samples. Over-representation analysis supported the same conclusion through an independent statistical route. To guard against the possibility that the finding was an artifact of their particular cohort, the researchers validated it in an independent dataset, GSE264573, and again found higher hallmark MYC pathway scores in tumor cells from castration-resistant samples compared with castration-sensitive ones. Together, these converging lines of evidence position MYC-driven transcriptional programs as a central feature of tumor cell adaptation in castration-resistant disease.

The emphasis on MYC is biologically coherent with prior mechanistic studies. In localized prostate cancer, MYC has been reported to cooperate with RAS signaling to promote bone metastasis and castration resistance, and a MYC/RAS co-activation signature has demonstrated predictive value across clinical cohorts. In neuroendocrine prostate cancer, an aggressive variant marked by loss of androgen receptor signaling, MYC activation has been associated with neuroendocrine differentiation, and alisertib, an Aurora-A kinase inhibitor that disrupts N-MYC stabilization, has shown clinical activity in a subset of neuroendocrine prostate cancer patients. Still, the authors are careful to note the limits of translation. MYC is not yet an established clinical biomarker in prostate cancer, its activity is not reliably captured by any single genomic alteration, and further studies are required to validate it as a robust prognostic and predictive tool. Moreover, other pathways, including PI3K/AKT signaling, may also contribute to castration resistance even if they were not prominently enriched in this dataset, reflecting the biological heterogeneity of metastatic disease, in which different tumors may rely on different dominant escape routes. The MYC-associated program identified here likely represents one major transcriptional state within a subset of patients rather than a universal mechanism.

The study also carries a molecular rationale for PSMA-targeted medicine. The significantly higher expression of FOLH1 in castration-resistant tumor cells provides single-cell-level support for the clinical efficacy of PSMA-directed therapies, most notably lutetium-177 PSMA-617 radioligand therapy, which has transformed the management of metastatic castration-resistant disease. The authors acknowledge the limitations inherent in their design: the number of castration-resistant samples was small, a constraint that reflects the genuine difficulty of obtaining metastatic specimens suitable for single-cell analysis, and functional validation will be needed to establish causal relationships between the observed transcriptional states and resistance. The analysis also did not systematically link tumor-cell changes to immune infiltration, clonal expansion, or T-cell receptor dynamics, information not available in the underlying dataset. Even so, by defining a transcriptional roadmap that spans from treatment-naïve disease through early hormonal therapy to full castration resistance, the study highlights two actionable features of tumor cell adaptation: a transient immune activation during ADT that could be exploited with timed immunotherapy combinations, and MYC-driven programs in resistant disease that may point toward new biomarker and drug development strategies aimed at delaying or preventing the emergence of lethal, treatment-resistant prostate cancer.

Subject of Research: Single-cell transcriptomic evolution of prostate cancer cells during androgen deprivation therapy and progression to castration resistance

Article Title: Single-cell analysis reveals tumor cell evolution from ADT-naïve to castration-resistant prostate cancer

Article References: Wei, Y., Wu, J., Wang, B., Gu, W., Qin, X., Dai, B., Lin, G., Gan, H., Wan, F., Zhu, Y., & Ye, D. (2026). Single-cell analysis reveals tumor cell evolution from ADT-naïve to castration-resistant prostate cancer. Holistic Integrative Oncology, 5(1), Article 39. https://doi.org/10.1007/s44178-026-00261-0

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00261-0

Keywords: prostate cancer, single-cell RNA sequencing, androgen deprivation therapy, castration resistance, MYC signaling, PSMA, FOLH1, interferon response, tumor evolution, immunotherapy timing, androgen receptor, metastatic cancer

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

Radioligand therapy with 177Lu-PSMA-617 has transformed the treatment landscape for metastatic castration-resistant prostate cancer, a lethal stage of the disease in which roughly half of patients survive less than five years after their metastatic diagnosis. The therapy exploits prostate-specific membrane antigen, a protein abundantly displayed on the surface of prostate cancer cells and further upregulated as tumors become castration resistant. A ligand called PSMA-617 delivers the beta-emitting radioisotope lutetium-177 directly to tumor cells, irradiating metastases throughout the body while sparing much of the surrounding healthy tissue. Following the landmark phase III VISION trial, the approach gained approval from the United States Food and Drug Administration in March 2022 for PSMA-positive patients who had already received an androgen receptor pathway inhibitor and taxane chemotherapy.

Yet the therapy has an uncomfortable secret: only about half of eligible patients derive meaningful clinical benefit. Except for PSMA PET imaging criteria used to confirm that tumors carry the target molecule, clinicians currently lack validated biomarkers to identify who will respond and who will progress despite treatment. This gap matters both scientifically and economically. A recent cost-effectiveness analysis based on the VISION trial concluded that adding 177Lu-PSMA to standard care may only be cost-effective under specific clinical and economic assumptions, underscoring the urgency of better patient selection.

To address this problem, investigators at IRCCS Istituto Romagnolo per lo Studio dei Tumori in Meldola, Italy, enrolled 145 patients between April 2017 and October 2022 in a prospective observational biological study nested within a single-arm phase II trial of 177Lu-PSMA-617. Of these, 142 patients received at least one dose and were fully evaluable. Within seven days of the first infusion, the researchers collected baseline blood samples and measured a panel of routinely available laboratory markers, including hemoglobin, alkaline phosphatase, prostate-specific antigen, chromogranin A, neuron-specific enolase, and CEA, along with inflammatory ratios derived from the complete blood count. All patients received treatment in four cycles administered every eight to twelve weeks, using either a lower activity of 3.7 to 4.4 gigabecquerels or a higher activity of 5.5 gigabecquerels per cycle.

At a median follow-up of 44 months, the cohort experienced a median progression-free survival of 7.0 months and a median overall survival of 16.8 months, outcomes broadly consistent with the pivotal VISION and TheraP trials. In univariable analyses, elevated platelet-to-lymphocyte ratio, alkaline phosphatase, PSA, and CEA each predicted shorter progression-free survival, while low hemoglobin and high neutrophil-to-lymphocyte ratio, along with the same markers, predicted shorter overall survival. But when the researchers integrated all clinical characteristics and serum biomarkers into multivariable Cox regression models, only a handful of factors retained independent significance: prior docetaxel exposure, low hemoglobin, high PSA, and, critically, elevated CEA. High CEA independently predicted both shorter progression-free survival, with a p-value of 0.026, and shorter overall survival, with a p-value of 0.003.

The statistical rigor of the analysis strengthens the claim. Multicollinearity checks using variance inflation factors confirmed that no variable simply duplicated another, with all values below two. When CEA was added to a model containing established prognostic factors, the overall model fit improved significantly according to a likelihood-ratio test, and Harrell’s concordance index rose from 0.732 to 0.742. Although PSA alone discriminated outcomes better than CEA alone, with C-indices of 0.652 versus 0.598, combining the two markers pushed the C-index to 0.694, demonstrating that CEA carries prognostic information that PSA does not capture. Exploratory correlation analyses reinforced this independence: baseline CEA showed essentially no relationship with PSA levels and only a weak association with chromogranin A, while it did not correlate with bone disease burden measured on PSMA PET scans.

The biological story behind elevated CEA may be as compelling as the statistics. CEA is an oncofetal glycoprotein long used as a tumor marker in colorectal and other cancers, and previous work has linked it to aggressive disease biology in prostate cancer. In particular, elevated serum CEA in castration-resistant prostate cancer has been associated with liver metastases, markedly shorter survival, and distinctive circulating tumor DNA alterations. It has also been tied to aggressive variant prostate cancer, a molecularly distinct and treatment-resistant phenotype. Although a single-arm design without a control group prevents the authors from claiming that CEA specifically predicts benefit from 177Lu-PSMA rather than simply flagging inherently aggressive disease, the finding raises the hypothesis that high CEA identifies a biologically distinct subgroup with intrinsic resistance to PSMA-targeted radioligand therapy. Notably, baseline FDG PET was not mandatory in this cohort, so the researchers could not test whether CEA-elevated patients harbored FDG-positive, PSMA-low lesions typical of aggressive variants.

Other markers behaved as expected. Lower hemoglobin, likely reflecting chronic inflammation and extensive bone marrow involvement rather than a direct effect on treatment response, remained independently associated with shorter overall survival. Alkaline phosphatase, a proxy for skeletal tumor burden, also independently predicted overall survival, consistent with three prior studies and a recent meta-analysis. Inflammatory ratios lost much of their significance after adjustment, although platelet-to-lymphocyte ratio retained an association with progression-free survival. An intriguing exploratory interaction suggested that the prognostic impact of CEA may differ according to the administered radiation activity, but the authors caution that this post hoc finding is hypothesis-generating only, since dose was not randomly assigned and lower activities were reserved for frailer patients.

The study’s limitations temper, but do not erase, its promise. The administered activities were lower than the currently approved Pluvicto regimen of 7.4 gigabecquerels every six weeks, potentially limiting generalizability, and no metastatic biopsies were available to histologically confirm neuroendocrine differentiation among patients with elevated chromogranin A or neuron-specific enolase, markers of limited specificity that can rise in many benign and malignant conditions. External validation in cohorts treated with the approved dosing schedule will be essential before CEA enters routine risk stratification. Still, the vision is clear: if validated, a marker already present on virtually every hospital laboratory requisition could, at essentially no added cost, help clinicians identify patients facing aggressive, inherently resistant disease, guide them toward alternative or combination strategies, and reserve this costly radioligand therapy for those most likely to benefit. In the precision oncology era, the humble CEA blood draw may prove an unexpectedly powerful ally.

Subject of Research: Baseline serum carcinoembryonic antigen as an independent prognostic biomarker for survival outcomes in metastatic castration-resistant prostate cancer patients treated with 177Lu-PSMA radioligand therapy

Article Title: Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy

Article References: Giunta, E. F., Marini, I., Grassi, I., Nicolini, S., Foca, F., Celli, M., Caroli, P., Sarnelli, A., Brighi, N., Schepisi, G., Monti, M., De Giorgi, U., Lolli, C., & Sansovini, M. (2026). Baseline serum carcinoembryonic antigen (CEA) is an independent prognostic biomarker for metastatic castration-resistant prostate cancer (mCRPC) patients receiving 177Lu-PSMA therapy. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08173-x

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08173-x

Keywords: 177Lu-PSMA, prostate cancer, radioligand therapy, CEA, biomarker, metastatic castration-resistant prostate cancer, prognostic factors, PSMA, overall survival, progression-free survival, PSMA-617, serum tumor markers

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