From State, Pathway, to Niche: The Ternary Network of Breast Cancer Stem-like Cells Driving Tumor Progression and Combination Therapy Prospects

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer.