Purpose <p>Despite advancements in ¹⁷⁷Lu-based radiotherapy for cancer, its efficacy against refractory cold tumors remains limited. Targeted peptide-radionuclide conjugates (PRCs) combined with immunotherapy are emerging as promising theranostic strategies to maximize anti-tumor effectiveness.</p> Methods <p>Cyclic peptide CEMJ4 was identified via phage selection, and further conjugated with DOTA and radiolabeled with ⁶⁸Ga for diagnostic imaging and ¹⁷⁷Lu for cancer therapy. The druggability was assessed by in vitro cell experiments, in vivo PET/CT imaging and biodistribution. Additionally, the feasibility of combining ¹⁷⁷Lu-DOTA-CEMJ4 with a hematopoietic progenitor kinase 1 inhibitor (HPK1i) was evaluated in B16F10 tumor-bearing mice, focusing on the anti-tumor immune response and tumor growth.</p> Results <p>CEMJ4 exhibited high affinity for human erythropoietin-producing hepatocellular receptor A2 (EphA2; <i>K</i>_<i>D</i> = 0.3 ± 0.2 µM), a therapeutic target overexpressed in several solid tumors. Radiolabeled ⁶⁸Ga/¹⁷⁷Lu-DOTA-CEMJ4 specifically bound to EphA2-expressing B16F10 cells and tumor models, effectively inhibiting tumor growth. Notably, ¹⁷⁷Lu-induced T cell immunotoxicity was reversed by HPK1i, which modulated T cell dysfunction. Combining ¹⁷⁷Lu-DOTA-CEMJ4 with HPK1i significantly reduced tumor burden and increased tumor-infiltrating CD4⁺ T cells, CD8⁺ T cells, and M1 macrophages.</p> Conclusion <p>This study identifies CEMJ4 as a promising peptide ligand for tumor-targeted radionuclide delivery and emphasizes the clinical potential of radionuclide therapy combined with immunotherapy in theranostics to enhance therapeutic precision and efficacy.</p> Graphical Abstract <p></p>