Advances in radiopharmaceuticals for cancer radiotheranostics: CCK2R targeting as a paradigm for translational innovation

Radiopharmaceuticals are reshaping the landscape of cancer therapy, offering a unique theranostic advantage that is becoming increasingly central to precision medicine. By labeling the same molecular scaffold with different radionuclides, these agents enable seamless integration of diagnostic imaging and targeted therapy. Clinical breakthroughs with somatostatin receptor subtype 2 (SSTR2)- and prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals have significantly enhanced both tumor visualization and therapeutic efficacy, establishing new benchmarks in oncology. Ongoing research is exploring novel molecular targets such as cholecystokinin-2 receptor (CCK2R), fibroblast activation protein (FAP), and C-X-C chemokine receptor type 4 (CXCR4). In parallel, there is growing interest in utilizing alternative radionuclides, including alpha-particle emitters and Auger electron emitters, beyond the commonly used beta-emitters, to improve therapeutic outcomes. Simultaneously, advances in ligand and linker design are being leveraged to optimize in vivo pharmacokinetics and tissue distribution. Among the emerging targets, CCK2R has attracted notable attention due to its overexpression in multiple malignancies. Research efforts have focused on improving ligand stability, receptor-binding affinity, and tumor retention, while also exploring strategies to enhance CCK2R expression on cancer cells. This review offers a comprehensive overview of the current landscape in cancer radiotheranostics, exploring the role of CCK2R in cancer biology and summarizing the latest advancements in the development of CCK2R-targeted radiopharmaceuticals. Using these advancements as a case study, we systematically examine key aspects of next-generation radiopharmaceutical design, from target selection and ligand engineering to pharmacokinetic optimization and clinical translation, providing a multidimensional framework for future innovation in cancer radiotheranostics.