Update information. Triple negative breast cancer (TNBC) is one of the most aggressive molecular subtypes in breast cancer. Due to the lack of effective therapeutic targets, the clinical outcomes for TNBC patients remain poor. Here, we performed an integrated proteomic analysis including bioinformatic analysis of proteome database, label-free proteomics, and immunoprecipitation coupled with mass spectrometry (IP-MS) to explore potential therapeutic targets for TNBC. Bioinformatic analysis showed that MAGE-D2 was overexpressed in TNBC. In vivo and in vitro experiments indicated that MAGE-D2 overexpression could promote TNBC proliferation and metastasis. In addition, label-free proteomics revealed that MAGE-D2 played a cancer-promoting role by activating PI3K/AKT pathway. Moreover, the results of IP-MS and cross-linking/xIP-MS demonstrated that MAGE-D2 could interact with Hsp70 and prevent Hsp70 degradation. Therefore, MAGE-D2 could be a potential therapeutic target for TNBC, and inhibiting MAGE-D2 may have important therapeutic relevance.