Radionuclide-Dependent Stimulation of Antitumor Immunity in GD2-Targeted Radiopharmaceutical Therapy Combined with...

Radiopharmaceutical therapy (RPT) offers tumor-selective radiation delivery and represents a promising platform for combination with immune checkpoint inhibitors (ICIs). While prior studies suggest that RPT can stimulate antitumor immunity, synergy with ICIs may depend on radionuclide properties, absorbed dose, and radiation distribution within the tumor microenvironment. This study evaluated how radionuclide selection and dose influence immune stimulation and therapeutic efficacy of GD2-targeted antibody-based RPT combined with ICIs. Dinutuximab, an anti-GD2 monoclonal antibody, was radiolabeled with β^--emitters (⁹⁰Y, ¹⁷⁷Lu) or an α-emitter (²²⁵Ac). C57Bl6 mice bearing GD2⁺ tumors received 4 or 15 Gy tumor-absorbed doses, determined by individualized dosimetry, with or without dual ICIs (anti-CTLA-4 and anti-PD-L1). In vivo imaging, ex vivo biodistribution, survival, histological, and gene expression analyses were performed to assess therapeutic and immunological outcomes. All radiolabeled constructs demonstrated preferential uptake in GD2⁺ tumors. Combination therapy improved survival in a radionuclide- and dose-dependent manner, with the greatest benefit in the ²²⁵Ac + ICI group at 15 Gy. Treatment activated type I interferon signaling and increased MHC-I and PD-L1 expression. Notably, ⁹⁰Y reduced regulatory T cells, enhancing CD8⁺/Treg ratios, while ²²⁵Ac induced robust interferon-driven activation. Radionuclide selection and absorbed dose critically shape immune and therapeutic outcomes of antibody-based RPT combined with ICIs, underscoring the importance of delivery mechanism and dose optimization in combination therapy strategies.