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Life sciences · Journal article
Journal of Translational Medicine · September 25, 2026
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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).