Colorectal cancer liver metastasis (CRLM) remains a leading cause of cancer-related mortality, with clinical outcomes limited by biological heterogeneity and inconsistent therapeutic responses. Despite advances in systemic chemotherapy, targeted agents, immunotherapy, and liver-directed interventions, the translation of preclinical efficacy into clinical benefit remains suboptimal, highlighting the need for predictive experimental models. However, therapeutic efficacy in CRLM is highly model-dependent, and discrepancies between preclinical findings and clinical outcomes often arise from differences in biological fidelity across experimental platforms. This review critically examines preclinical platforms used to study CRLM, with emphasis on orthotopic and metastatic models that recapitulate hepatic colonization, tumor–microenvironment interactions, and immune regulation. We evaluate methodological innovations that enhance anatomical fidelity and reproducibility, including tissue adhesive–based implantation and biomaterial-assisted strategies. Importantly, we analyze how different models influence therapeutic assessment across systemic, immune-based, metabolic, and liver-directed treatments, and discuss their ability to predict clinical responses. By integrating insights from experimental studies with key clinical evidence, we delineate the strengths and limitations of current platforms and propose principles for rational model selection to improve translational success in CRLM research.

Radiopharmaceuticals deliver diagnostic or therapeutic radionuclides to disease sites with molecular precision. Over the past five years, clinical adoption has accelerated, led by U.S. Food and Drug Administration approvals of ¹⁷⁷Lu-DOTA-TATE and ¹⁷⁷Lu-PSMA-617 and their complementary Positron Emission Tomography agents (⁶⁸Ga-DOTA-TATE, ⁶⁸Ga-PSMA-11), which have established radiotheranostics as a pillar of oncology care. The new generation of agents couples optimized radionuclides (β⁻, α, and Auger emitters) to antibodies, peptides, and small-molecule vectors that improve tumor uptake, residence time, and clearance profiles, thereby enhancing efficacy and safety. Beyond neuroendocrine tumors and prostate cancer, radiotheranostic strategies are advancing for diverse malignancies by exploiting tumor-specific antigens, overexpressed receptors, and intracellular targets. Notably, α-emitters such as ²²⁵Ac and ²¹¹At—owing to high linear energy transfer and short path length—show potent cytotoxicity with limited off-target injury, while emerging β/Auger emitters like ¹⁶¹Tb may surpass ¹⁷⁷Lu in microdosimetric effectiveness. Concurrent innovations in patient selection and response prediction leverage diagnostic radiopharmaceuticals for image-guided stratification, individualized dosimetry, and adaptive treatment planning, supporting the broader paradigm of precision medicine. Although oncology remains the primary focus, applications are expanding to neurodegeneration, cardiovascular disease, and inflammatory conditions. This review synthesizes technological and clinical progress from 2021–2025, spanning FDA-approved and late-stage investigational agents; mechanisms of radiopharmaceutical-induced cell death; dosimetry methodologies; trial landscapes for expanding indications; and translational challenges, including supply chains, chelation chemistry, and toxicity management. Accordingly, this review focuses on the latest radiopharmaceutical diagnostic and therapeutic technologies, integrating advances in radionuclide platforms, targeting vectors, dosimetry, and clinical trial data from 2021–2025 to guide future development and clinical implementation of precision radiotheranostics.