Background <p>[¹⁷⁷Lu]Lu-DOTA-TATE is an effective treatment for metastatic neuroendocrine tumors (NETs) expressing somatostatin receptors. While the tumor uptake [¹⁷⁷Lu]Lu-DOTA-TATE of has shown potential as a predictive biomarker, patient response to the treatment varies significantly. In this study, we aim to identify a predictive blood-based transcriptomic biomarker to better understand individual responses to [¹⁷⁷Lu]Lu-DOTA-TATE therapy.</p> Results <p>Twenty-six patients were prospectively enrolled in this study. Responders were defined as patients who showed partial response or stable disease and non-responders were defined as patients who showed progressive disease according to RECIST1.1 criteria. Of the 26 patients, responders (n = 20) exhibited distinct gene expression profiles compared to non-responders (n = 6). Among the 21 differentially expressed genes identified between the groups, 13 genes were upregulated in non-responders and were associated with the innate immune system. Weighted Gene Co-expression Network Analysis identified a significant gene module linked to treatment response, with eEF1A1 emerging as a key hub gene correlated with favorable outcomes. Baseline clinical and laboratory parameters did not differ significantly according to treatment response.</p> Conclusions <p>This study identifies specific blood transcriptomic profiles associated with the innate immune response and a key hub gene linked to treatment outcomes, suggesting an immune-related component in response to [¹⁷⁷Lu]Lu-DOTA-TATE therapy. These findings may guide patient selection based on systemic immune markers and inform future therapeutic strategies.</p>