Aim <p>Luminal breast cancer (BC) is the most common subtype of BC. This study aimed to clarify the role of NRBP2 in luminal BC progression and its potential interaction with tamoxifen therapy.</p> Main methods <p>In vivo and in vitro models were employed to assess the impact of NRBP2 expression modulation on tumor growth and its association with tamoxifen treatment. Autophagic flux was evaluated using electron microscopy, confocal microscopy, and specific pathway inhibitors. The NRBP2-driven LKB1/AMPK/ULK1 signaling axis was investigated via Western blotting and immunohistochemistry. Clinical relevance was assessed using public databases and a validated cohort of 138 luminal BC patients.</p> Results <p>Our findings demonstrate that NRBP2 functions as a tumor suppressor, as its overexpression significantly induced apoptosis in vitro and tumour regression was observed in vivo. Mechanistically, NRBP2 acts as a positive regulator of the LKB1/AMPK/ULK1 autophagic signaling axis, promoting autophagic flux. Notably, NRBP2 overexpression significantly enhanced the sensitivity of luminal BC cells to tamoxifen treatment. Functional rescue experiments revealed that the enhanced combined pro-apoptotic effect of NRBP2 and tamoxifen was effectively abrogated upon autophagy inhibition. Clinical analysis revealed that NRBP2 expression levels were positively correlated with the expression of key autophagic markers (p-ULK1 and Beclin 1) and that high NRBP2 expression was associated with improved relapse-free survival.</p> Conclusions <p>Our findings establish that NRBP2 enhances tamoxifen sensitivity in luminal breast cancer through a process functionally driven by the activation of the LKB1/AMPK/ULK1/autophagy axis, highlighting NRBP2 as a potential therapeutic target to enhance the efficacy of endocrine-based treatment strategies.</p> Graphical Abstract <p></p>