B7-H4–targeted radiotheranostics enable precise imaging and potent therapy across solid tumor models

B7-H4 is an emerging immunoregulatory checkpoint broadly overexpressed across solid tumors and minimally present in normal tissues, making it an attractive candidate for targeted imaging and therapy. Here, we develop and evaluate a B7-H4–directed radiotheranostic antibody labeled with [ ⁸⁹ Zr] for PET imaging and with either [ ¹⁷⁷ Lu] or [ ²²⁵ Ac] for β- or α-particle therapy, respectively. [ ⁸⁹ Zr]-immunoPET enabled quantitative, whole-body visualization of B7-H4 expression and reliably distinguished high, intermediate, and negative-expressing tumors. Radiotherapy with [ ¹⁷⁷ Lu]- or [ ²²⁵ Ac]-conjugated antibody exhibited potent, antigen-dependent antitumor activity, including complete and durable regressions in B7-H4–high expressing xenografts after a single administration, while having a minimal effect on B7-H4–negative tumors. Both therapeutic constructs were well tolerated, causing only transient, reversible myelosuppression without sustained hepatic, renal, or histopathologic toxicity. These findings identify B7-H4 as a promising target for integrated imaging and radionuclide therapy and provide a preclinical foundation for the future development of B7-H4–directed radiotheranostic strategies.