Simple SummaryBreast cancer is a complex disease that remains a significant public health challenge. The breast cancer cells secrete various substances collectively known as the secretome, which include proteins, lipids, and nucleic acids that contribute to the growth and spread of breast cancer. The secretome plays a crucial role in the development and progression of breast cancer by modifying signaling pathways and creating an environment supporting cancer growth while evading the immune system. Additionally, the secretome is responsible for the development of resistance to cancer drugs, making it a significant challenge for effective treatment. Therefore, understanding the role of the secretome in breast cancer is essential for developing innovative therapies. This review provides insights into the impact of the secretome on breast cancer progression and its interactions with the tumor microenvironment, and explores potential therapeutic opportunities targeting the secretome components. By identifying specific molecules and signaling pathways involved in the secretome, new targets for therapeutic intervention can be identified, which can ultimately improve outcomes for breast cancer patients.AbstractBreast cancer is a complex and heterogeneous disease resulting from the accumulation of genetic and epigenetic alterations in breast epithelial cells. Despite remarkable progress in diagnosis and treatment, breast cancer continues to be the most prevalent cancer affecting women worldwide. Recent research has uncovered a compelling link between breast cancer onset and the extracellular environment enveloping tumor cells. The complex network of proteins secreted by cancer cells and other cellular components within the tumor microenvironment has emerged as a critical player in driving the disease’s metastatic properties. Specifically, the proteins released by the tumor cells termed the secretome, can significantly influence the progression and metastasis of breast cancer. The breast cancer cell secretome promotes tumorigenesis through its ability to modulate growth-associated signaling pathways, reshaping the tumor microenvironment, supporting pre-metastatic niche formation, and facilitating immunosurveillance evasion. Additionally, the secretome has been shown to play a crucial role in drug resistance development, making it an attractive target for cancer therapy. Understanding the intricate role of the cancer cell secretome in breast cancer progression will provide new insights into the underlying mechanisms of this disease and aid in the development of more innovative therapeutic interventions. Hence, this review provides a nuanced analysis of the impact of the cancer cell secretome on breast cancer progression, elucidates the complex reciprocal interaction with the components of the tumor microenvironment and highlights emerging therapeutic opportunities for targeting the constituents of the secretome.