PSMA-targeted radiopharmaceutical therapy (RPT) is a standard treatment for metastatic castration-resistant prostate cancer (PCa), exploiting PSMA overexpression to deliver cytotoxic radiation. Treatment with the β-emitter [¹⁷⁷Lu]Lu-PSMA-617, approved in 2022, has been associated with prolonged progression-free and overall survival in patients with PCa. However, resistance and heterogeneous patient responses limit its efficacy. Although immunotherapy is effective in several malignancies, PCa’s immunosuppressive microenvironment often reduces its impact. Combining targeted RPT with immune checkpoint inhibitors, particularly programmed cell death protein 1 and programmed cell death ligand 1 inhibitors, may enhance antitumor responses. This review explores the rationale behind this combination, evaluates preclinical and clinical evidence, and discusses future directions for integrating immune checkpoint blockade with targeted RPT. Visual Abstract

Molecularly targeted therapies are increasingly relevant in clinical oncology, as they enable the selective modulation of specific biologic targets—such as enzymes or receptors—by inhibiting or enhancing their function. Nectin cell adhesion molecule 4 (nectin-4), a tumor-associated antigen, is overexpressed in various malignancies and has been linked to tumor progression and poor clinical outcomes. Its role has recently gained significant attention, particularly in urothelial carcinoma, where nectin-4–targeted antibody–drug conjugates have demonstrated promising therapeutic efficacy. These findings have positioned nectin-4 not only as a relevant target for noninvasive tumor characterization and cancer therapy but also as a valuable biomarker for molecular imaging. This review provides an overview of the recent developments in nectin-4–directed molecular theranostics, on the basis of a literature analysis, with a focus on the design, preclinical validation, and clinical translation of novel radiotracers in nuclear medicine. Multiple nectin-4–targeted radiotracers—comprising antibody- and peptide-based agents—have demonstrated high specificity and strong affinity for nectin-4–overexpressing tumors, particularly in urothelial carcinoma and triple-negative breast cancer. Exploratory preclinical and clinical data consistently showed comparable diagnostic accuracy to standard molecular imaging methods (e.g., [¹⁸F]FDG-based PET), enhanced detection of metastatic lesions, and effective monitoring of therapeutic response and eventual treatment resistance to nectin-4–targeted antibody–drug conjugates. Visual Abstract

Background: Radiolabeled fibroblast activation protein inhibitors (FAPIs) have emerged as novel radiopharmaceutical agents for tumor diagnosis. Compared with [¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), which reflects glucose uptake in metabolically active regions, FAPIs mainly bind to the fibroblast activation protein (FAP), which is highly expressed in tumor-associated fibroblasts, forming a pronounced signal. Several studies suggested potential superiority of FAPI tracers above [¹⁸F]FDG-based imaging in a variety of tumor entities. In this systematic review, we focus on the comparison of FAPI-PET/CT and [¹⁸F]FDG-PET/CT in upper-abdominal tumors. Methods: Original research published from 1 January 2021 to 22 December 2024 was collected from the PubMed and Web of Science databases (CRD42025648267). This research included only clinical studies, excluding conference abstracts and case reports. The risk of bias was assessed with the QUADAS-2 tool, and all evaluation steps performed independently by three independent reviewers. A systematic quality assessment of the included studies was conducted based on the imaging performance of FAPI-PET/CT and [¹⁸F]FDG-PET/CT for pancreatic, liver, and gastric cancers. The meta-analysis used relative risk (RR) as the effect size, with bias assessed via the Peters test (p-value > 0.05). Cochran’s Q test and I-squared value are used to comprehensively evaluate the magnitude of heterogeneity. Analyses and data visualization were performed in R language. Results: The database search identified 3272 articles. After screening, 31 studies were included in this analysis. The original studies enrolled 1377 participants (M/F: 850/527; ages predominantly between 50 and 70). Of these, 939 patients were ultimately diagnosed with tumors (five cancer subtypes) and included in this analysis. Meta-analysis results showed that FAPI-PET/CT significantly surpassed [¹⁸F]FDG-PET/CT in the detection of primary lesions (RRs = 1.20 and 1.17), lymph nodes (RRs = 1.18 and 1.24), distant metastases (RRs = 1.22 and 1.51), peritoneal metastases (RRs = 1.31 and 2.22), and bone metastases (RRs = 1.16 and 1.23). The two imaging methods exhibit clear differences in diagnostic performance (sensitivity: 98% vs. 79%; specificity: 83% vs. 87%), and FAPI-PET/CT demonstrates high and stable diagnostic performance (RRs = 1.20 and 1.17). Conclusions: Compared with [¹⁸F]FDG-PET/CT, FAPI-PET/CT demonstrates significant advantages in detecting primary lesions, lymph nodes, distant metastases, and peritoneal and bone metastases in pancreatic, liver, and gastric cancers (RR > 1.0). Overall, FAPI-PET/CT shows better diagnostic performance (RR > 1.0).

Background: Glioblastoma is known for its highly immunosuppressive microenvironment, hindering the efficacy of immunotherapies. Noninvasive imaging like immuno-positron emission tomography (PET) offers the potential for visualizing immune dynamics within glioblastoma, potentially aiding in patient selection and treatment monitoring. This systematic review evaluates immuno-PET tracers currently under investigation for the noninvasive visualization of the immune environment in glioblastoma. Methods: A literature search was conducted in PubMed and Web of Science up to March 2025, using keywords related to glioblastoma, immuno-PET, immune compartments, and specific tracers. Studies were screened based on predefined inclusion and exclusion criteria, focusing on the development, characterization, or application of immuno-PET tracers targeting immune cells or immune checkpoint molecules in glioblastoma. Results: Nineteen studies met the inclusion criteria, exploring tracers targeting immune checkpoints and immune cell populations. Full-length antibodies demonstrated higher tumor specificity and retention compared to smaller fragments but showed longer circulation times. Peptide-based tracers and affibodies offered improved pharmacokinetics with rapid clearance and lower nonspecific uptake but encountered hurdles in ensuring adequate tumor targeting and retention. Advancements included dual-modal tracers combining PET and near-infrared fluorescence imaging for enhanced diagnostic and intraoperative applications. Conclusions: Significant progress has been made in developing immuno-PET tracers for noninvasive visualization of immune reactions in glioblastoma. Challenges persist in clinical translation due to issues like blood–brain barrier permeability and safety profiles. Continued research and clinical evaluations are essential to harness the potential of immuno-PET in improving glioblastoma diagnosis, assessment of treatment response, and guiding personalized immunotherapy strategies, ultimately aiming to enhance patient outcomes.

Background Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (PSMA-RGS) is a promising intraoperative technique for improving lesion localization and surgical accuracy in prostate cancer (PCa), particularly in high-risk or recurrent cases. Objective To systematically evaluate the diagnostic performance of PSMA-RGS in PCa using multilevel meta-analysis. Methods Following PRISMA 2020 guidelines, we searched PubMed, Embase, and Web of Science for clinical studies published between January 2016 and May 2025, with the final search performed on May 1, 2025, and identified 28 eligible studies. Diagnostic accuracy was assessed at the patient, lesion, region, and lymph node levels, using pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratios (DOR). Random-effects meta-analyses were conducted and risk of bias was evaluated with the ROBINS-I tool. Results Ex vivo PSMA-RGS demonstrated the highest specificity (up to 100%), while in vivo PSMA-RGS showed excellent sensitivity (90–97%) and specificity (90–99%), particularly at the lymph node level. Across all evaluated anatomical levels, PSMA-RGS consistently outperformed preoperative imaging (log DOR: 5.77 vs. 2.99; p < 0.0001). All diagnostic results were confirmed by histopathology as the reference standard. Meta-regression identified in vivo PSMA-RGS, lymph node–based analysis, and γ-probes combined with high-purity germanium detectors—used for post-resection confirmation—as independent predictors of improved diagnostic performance. Conclusion PSMA-RGS demonstrates robust diagnostic accuracy across multiple analytical levels, including per-patient, per-lesion, and per-node assessments. Initial evidence suggests that intraoperative γ-probes guidance may enable real-time localization of otherwise undetected nodal metastases. In high-risk prostate cancer surgery, this approach may help refine intraoperative decision-making, improve resection completeness, and reduce recurrence.