Purpose <p>The overexpression of somatostatin receptor (SSTR) in neuroendocrine neoplasms (NENs) provides a molecular basis for treatment with peptide receptor radionuclide therapy (PRRT). However, heterogeneous SSTR expression limits therapeutic efficacy. Immune checkpoint inhibitors (ICIs) enhance the abscopal effect of external radiotherapy. This study investigated whether combining PRRT using the SSTR antagonist [¹⁷⁷Lu]Lu-DOTA-JR11 with anti-PD-L1 monoclonal antibody (mAb) therapy could enhance the abscopal effect in an SSTR2-heterogeneous bilateral tumor model.</p> Methods <p>A bilateral SSTR2-heterogeneous murine melanoma model was established by contralateral implantation of B16F10-SSTR2 and B16F10-wildtype tumors. Mice received saline, PRRT, anti-PD-L1 mAb, or combination therapy. Tumor growth, survival, PET/CT imaging, histopathology, immune profiling (including PD-L1 expression, CD45⁺ cells, CD8⁺ cells, myeloid-derived suppressor cells [MDSCs], and macrophage phenotypes), and serum cytokine levels were assessed to evaluate local and systemic antitumor responses.</p> Results <p>PRRT monotherapy selectively inhibited SSTR2-positive tumors but showed minimal efficacy against SSTR2-negative tumors. Combination therapy significantly suppressed the growth of both tumors, prolonged survival, and reduced [¹⁸F]FDG uptake in tumors. These effects were accompanied by increased Granzyme B expression, enhanced CD8⁺ cell infiltration, expansion of M1 macrophages and effector memory T cells, and reductions in MDSCs and M2 macrophages. Serum IFN-γ and IL-2 levels were significantly elevated, indicating robust systemic immune activation.</p> Conclusion <p>PRRT combined with PD-L1 blockade remodels the tumor immune microenvironment, elicits potent systemic antitumor immunity, and enhances the abscopal effect in SSTR2-heterogeneous tumors. This strategy may help address target-expression heterogeneity in radionuclide therapy.</p>