Cell competition within breast tumor microenvironment: emerging role of cancer stem cells and immune cells in tumor progression and therapeutic implications
This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME and identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.
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.
Bladder cancer is characterized by a highly dynamic tumor microenvironment (TME) that critically influences tumor progression, immune evasion, and therapeutic responsiveness. Among the immune populations in the TME, regulatory T cells (Tregs) play a central role in maintaining immune tolerance but also suppress effective antitumor immunity. Increasing evidence suggests that Tregs accumulate in bladder tumors and are associated with disease progression and reduced response to immunotherapies. The bladder cancer TME provides multiple signals that promote Treg recruitment, expansion, and functional stabilization, including chemokine-mediated trafficking, metabolic adaptation, and cytokine-driven differentiation. Interactions between Tregs and other microenvironmental components, such as cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and extracellular matrix elements, further reinforce the immunosuppressive niche that facilitates tumor survival and therapy resistance. Recent advances in single-cell transcriptomics, spatial profiling, and multiomics analyses have revealed substantial heterogeneity among tumor-infiltrating Tregs, suggesting the existence of specialized subsets with distinct functional and metabolic properties in the bladder TME. These emerging insights highlight the importance of understanding Treg–TME crosstalk in shaping the immune landscape of bladder cancer. Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy. This review summarizes recent advances in Treg biology in bladder cancer and highlights potential therapeutic strategies to modulate Treg-mediated immunosuppression in the TME.
Yusuke Fukiage, Nodoka Okubo, M. Taga et al.· Frontiers in Molecular Biosc...· 0 citations
This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Jia Li, Jinling Li, Yuechao Zhao et al.· Frontiers in Immunology· 0 citations
Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, resulting in limited targeted therapeutic options and poor clinical outcomes. Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of TNBC, therapeutic responses remain restricted to a subset of patients due to substantial heterogeneity within the tumor immune microenvironment (TIME). Increasing evidence indicates that immune evasion in TNBC is driven by complex interactions among tumor cells, immune populations, stromal components, and metabolic alterations. This review summarizes the dynamic landscape of the TNBC immune microenvironment, focusing on the functional roles of tumor-infiltrating lymphocytes, tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, and myeloid-derived suppressor cells in regulating antitumor immunity and therapeutic resistance. We further discuss clinical advances of ICIs, including monotherapy and chemoimmunotherapy approaches, as well as emerging therapeutic strategies involving small molecules, bispecific antibodies, antibody–drug conjugates, and novel immune-based modalities.
Hong-Yu Cao, Mei Tao, Xueyi Qin et al.· Frontiers in Immunology· 0 citations
Plastic features of BCSCs are summarized, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies are summarized and progress toward subtype-specific combination approaches is indicated.
Mu-Yao Li, Ying Zhou, Xin-Qi Liu et al.· Cancer Advances· 0 citations
Cancer stem cells (CSCs) are a small population of cells within a tumor which perform stem cell like functions including self-renewal, differentiation and initiation. This narrative review aims to provide an overview of the role of CSCs in resistance to standard treatment and metastasis in breast cancer, potential treatment strategies including latest clinical trials, and the clinical implications for CSCs in the management of breast cancer. The most established breast CSC markers (CD44+/CD24- and ALDH1) are most prevalent in basal-like cancers, the most aggressive subtype of breast cancer. The most implicated CSC pathways include Hedgehog, Notch, CXCR1, and Wnt. Previous phase I/II trials targeting these pathways associated with breast CSCs have shown mixed results; no CSC-specific drug has reached phase III trial in breast cancer. To maximize the potential benefit of CSC-targeted therapy, it would be important to select or enrich patients with CSC markers or CSC-associated pathway activation. It would also be critical to develop combination strategies that overcome plasticity and/or immune invasion, and preferentially destroy CSCs with limited impact on healthy stem cells. Overall, breast CSCs may have greater clinical implications but require further research and development to realize their full clinical potential.
This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses, and highlights the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.
Paromita Sarker, Shreyas S Rao· Biochimica et biophysica act...· 0 citations