Optimized dosing of spatially heterogeneous radiopharmaceutical therapy reprograms poorly immunogenic tumors to enhance response to immune checkpoint blockade

Optimized lutetium-177 radiopharmaceutical therapy dosing that preserves low-dose TME regions (V90%<2.5 Gy) while delivering high-dose hotspots (V10%>20 Gy) reprograms poorly immunogenic murine tumors to respond to immune checkpoint blockade.

• Why it matters: ICIs fail in poorly immunogenic tumors because effector T cells are excluded or exhausted and tumor-specific T cells are inadequately primed, and the best RPT dosing strategy for combination therapy is unclear.
• What they did: In multiple lutetium-177 RPT plus ICI preclinical models, activities were selected using TME dose heterogeneity metrics rather than mean absorbed dose, then assessed with spatial transcriptomics at day 7 and serial tumor biopsies.
• The result: The optimized dosing produced heterogeneous tumor marker dose-response patterns and localized dendritic cell migratory signals, sustained cDC1 activation in tumor-draining lymph nodes, expanded antigen-specific CD8 T cells systemically, and increased effector T-cell recruitment and inflammatory cytokines in the TME.