Antibody-Radionuclide Conjugates for Solid Tumors: Multidimensional Strategies from Component Engineering to Synergistic Combination Therapy

Abstract

Antibody-radionuclide conjugates (ARCs), defined as systems in which antibodies or their derivatives are linked to therapeutic or diagnostic radionuclides via covalent or non-covalent strategies, represent a promising platform for precision tumor theranostics. Their clinical application in solid tumors, however, remains constrained by poor tumor penetration, heterogeneous antigen expression, off-tumor toxicity, and an immunosuppressive tumor microenvironment. To systematically address these barriers, multidimensional strategies are being pursued. Structurally, innovations in radionuclide selection, antibody engineering, and chelator chemistry are enhancing targeting efficacy and in vivo stability. Strategically, pretargeting approaches decouple antibody localization from radionuclide delivery to minimize off-target exposure. Systematically, matched theranostic pairs enable image-guided patient stratification and personalized dosimetry. Biologically, combining ARCs with immune checkpoint inhibitors or DNA damage response inhibitors remodels the tumor microenvironment and converts localized radiation into systemic antitumor immunity. This review critically evaluates recent advances across these domains, from component optimization, pretargeting strategies, and theranostic integration, to combination regimens, and highlights the translational barriers that must be overcome to realize the full clinical potential of ARCs in solid tumors.