RANKL inhibition potentiates bone-targeted radioligand therapy in lung cancer metastases: a translational study

The therapeutic efficacy of bone-seeking radiopharmaceuticals depends not only on radiation dosimetry but also on the biological stability of the skeletal microenvironment. Here, we highlight a biological paradox wherein high-dose β − irradiation from the novel radioligand [ 177 Lu]Lu-P15-073 may affect the bone niche and contribute to disease progression. We aim to dissect this mechanism and evaluate a mechanistically driven combination strategy to mitigate this effect. We integrated an A549 intratibial xenograft model of bone metastasis combined with quantitative proteomics to elucidate the microenvironmental impact of [ 177 Lu]Lu-P15-073. To counteract therapy-associated niche remodeling, we evaluated a concurrent combination strategy using RANKL inhibition. Preliminary clinical outcomes and morphological imaging data from a registered cohort of patients with bone-metastatic lung cancer were analyzed to assess translational relevance. While [ 177 Lu]Lu-P15-073 showed sustained retention in intratibial xenografts, monotherapy was associated with a higher pulmonary metastatic burden at the experimental endpoint. Proteomic and structural analyses indicated that therapeutic radiation was associated with osteoclastogenesis and lipid-metabolic reprogramming (upregulation of FABP4 , and PLIN1 ), cortical bone degradation, and pulmonary metastatic burden. Concurrent RANKL blockade was associated with attenuation of these changes and preservation of skeletal integrity. The niche-stabilizing strategy was associated with a lower pulmonary metastasis (incidence: 25% in combination, compared to 87.5% in monotherapy and 75% in controls) and a significantly longer median survival (> 50 vs. 37.5 days; P < 0.01). Translational imaging showed heterogeneous remodeling patterns, with the representative denosumab-exposed lesion showing osteogenic repair and the representative monotherapy lesion showing progressive osteolysis. Radiation-driven osteolysis and lipid reprogramming may represent factors that limiting the efficacy of bone-targeted monotherapy. Concurrent RANKL inhibition may help stabilize the skeletal microenvironment and reduce the pulmonary metastatic burden observed in this model. These findings provide a preclinical rationale for further evaluation of RANKL inhibition with bone-seeking radioligands. Preliminary clinical evaluation of 177 Lu labeled phosphonates (ChiCTR2300077313, Registered at 5 November, 2023).