NID2 drives paclitaxel resistance in triple-negative breast cancer via an LDHA-lactate-histone lactylation axis.

Paclitaxel resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC). Nidogen-2 (NID2), an extracellular matrix protein, has been implicated in tumor progression, but its contribution to taxane response is unclear. Here, we integrate patient-derived evidence with mechanistic experiments to delineate the role of NID2 in paclitaxel resistance. In TNBC patient data, higher NID2 is associated with reduced paclitaxel sensitivity and increased histone lactylation signatures. In SUM149 models, NID2 silencing decreases glycolytic output, lowers extracellular lactate, and reduces global lysine lactylation, including H3K18la and H3K9la. These changes are accompanied by downregulation of key glycolysis and lactate-transport components (LDHA and MCT1) and a marked increase in paclitaxel responsiveness. In xenograft tumors, NID2 knockdown similarly suppresses glycolysis- and lactylation-related proteins and enhances the antitumor effect of paclitaxel, whereas paclitaxel alone shows limited impact on the lactylation axis. Together, our findings identify NID2 as a stromal-metabolic regulator that promotes a lactate-histone lactylation program linked to paclitaxel resistance in TNBC, and suggest NID2 as a potential target to improve taxane efficacy.