Cell competition within breast tumor microenvironment: emerging role of cancer stem cells and immune cells in tumor progression and therapeutic implications

Abstract

Breast cancer remains the most prevalent malignancy among women worldwide, with approximately 2.3 million new cases diagnosed annually, accounting for nearly 12% of all cancer diagnosis globally. Increasing evidence highlights the tumor microenvironment (TME) as a dynamic and interactive ecosystem that governs tumor behaviour. This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME. We examine how breast cancer stem cells (BCSCs), defined by CD44+/CD24- phenotype and elevated ALDH activity, acquire enhanced fitness through MYC amplification and dysregulation of Hippo/YAP, Wnt/β-catenin and Notch signaling pathways. In parallel, we analyze the role of immune cell populations including tumor-associated macrophages, cytotoxic T lymphocytes, natural killer cells and myeloid-derived suppressor cells in shaping competitive interactions through resource limitation and immuno-suppressive signaling. We further explore metabolic competition, highlighting the Warburg effect, reverse Warburg effect and lactate-mediated immuno-suppression as central regulators of cellular fitness, alongside contributions from cancer-associated fibroblasts, extracellular matrix remodeling and exosome-mediated communication. The novelty of this study lies in integrating cellular, metabolic and stromal dimensions of competition into a unified framework and extending the concept beyond tumor cells to include immune and non-cellular components. Cumulatively, this study identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.