ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation.

Triple-negative breast cancer (TNBC) faces therapeutic challenges due to limited treatment options and frequent chemoresistance. In this study, we identify ATP6V0D2 as a key factor upregulated in TNBC, where its expression correlates with poor prognosis. Transcriptomic and functional analyses linked ATP6V0D2 to PI3K/AKT signaling and platinum drug resistance. Mechanistically, ATP6V0D2 enhanced lysosomal function to promote degradation of the tumor suppressor PHLPP2, thereby sustaining AKT phosphorylation. Functional assays showed that ATP6V0D2 knockdown increased cisplatin sensitivity both in vitro and in vivo. Furthermore, pharmacological inhibition of V-ATPase with bafilomycinA1 sensitized TNBC patient-derived organoids to cisplatin. Clinically, our analysis of 91 TNBC patients who received cisplatin-based neoadjuvant chemotherapy found that high ATP6V0D2 expression was inversely correlated with pathological complete response (pCR), whereas PHLPP2 levels showed positive association, supporting the proposed mechanistic link. Together, these findings highlight the impact of ATP6V0D2 on TNBC progression and cisplatin sensitivity, nominating ATP6V0D2 as a promising therapeutic target.