Abstract:
Despite recent advancements in research, cancer metastasis and recurrence continue to be the primary causes of treatment failure. In this context, tumor progression and treatment resistance are progressively inferred as consequences of complex dynamic crosstalk within the tumor microenvironment (TME), rather than being solely driven by tumor-intrinsic factors. The present study comprehensively explores the interactions between cancer stem cells (CSCs), tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) with a focus on breast malignancies. These findings reveal that CSCs play a pivotal role to actively reshape the immune landscape by exuding immunosuppressive cytokines like (Transforming Growth Factor-β) TGF-β, that in turn promotes the expansion of regulatory T cells (Tregs), thereby facilitating tumour immune escape. Concurrently, TAMs are polarized toward a pro-tumorigenic phenotype that suppresses cytotoxic T cell activity supporting tumor progression and metastasis.
Delineating in-silico model analyses of immune checkpoint, we further identified that CSC-associated molecular signature is significantly correlated with poor response to immunotherapy approaches, suggesting underlying theory of treatment resistance. Mechanistically, in breast cancer, we characterised a FOXC1–OCT4/SOX2 feedforward loop that sustains stemness and contributes significantly to chemoresistance. Moreover, this axis is negatively regulated by hsa-miR-5688; modulaion of which notably reduces stemness along with enhancing therapeutic sensitivity.
In conjunction, a crucial, focusable axis involving CSCs, TAMs, and TILs in cancer immunoediting and therapy resistance are featured in our investigation. These findings underscore the critical need to combinatorial therapeutic approaches that simultaneously remodel the TME, inhibiting CSC-driven signaling pathways, and immune-restoration to enhance clinical efficacy. Therefore, the detailed mechanistic insight gained from this study support enhanced therapeutic sensitivity and optimized patient outcome, targeting CSC, Immune cells and tumour microenvironment
