Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies

Abstract

Cancer stem cells (CSCs) have emerged as key contributors to tumor initiation, growth, and metastasis. In addition, CSCs play a significant role in inducing immune evasion, thereby compromising the effectiveness of cancer treatments. The reciprocal communication between CSCs and the tumor microenvironment (TME) is observed, with the TME providing a supportive niche for CSC survival and self-renewal, while CSCs, in turn, influence the polarization and persistence of the TME, promoting an immunosuppressive state. Consequently, these interactions hinder the efficacy of current cancer therapies, necessitating the exploration of novel therapeutic approaches to modulate the TME and target CSCs. In this review, we highlight the intricate strategies employed by CSCs to evade immune surveillance and develop resistance to therapies. Furthermore, we examine the dynamic interplay between CSCs and the TME, shedding light on how this interaction impacts cancer progression. Moreover, we provide an overview of advanced therapeutic strategies that specifically target CSCs and the TME, which hold promise for future clinical and translational studies in cancer treatment.

Keywords: Cancer immunotherapy; Cancer stem cell (CSC); Immune evasion; Myeloid-derived suppressor cells (MDSC); Therapy resistance; Tumor microenvironment (TME); Tumor-associated macrophage (TAM).

Fig. 1

CSC-induced tumorigenesis models. A Classical CSC Model. CSCs exhibit asymmetric division, resulting in CSC renewal and the generation of less tumorigenic non-CSC daughter cells. B Plastic CSC Model. Tumor microenvironment shapes CSC plasticity, explaining bidirectional conversion between CSC and non-CSC. C Monophyletic CSC Model. Inflammation and wound-healing signals impact aberrant differentiation and dynamic changes in tumor pathology

Fig. 2

The influence of TME on CSCs. The figure shows the TME components and their influence on CSCs, including the influence of stromal cells, ECM, immunosuppressive cells, and TME secretome. CAF, cancer-associated fibroblast; Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; ECM, extracellular matrix; IL-6, interleukin-6; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; TGF-β, transforming growth factor-beta; VEGF, vascular endothelial growth factor; CXCL12, C-X-C motif chemokine ligand 12; bFGF, basic fibroblast growth factor; HA, hyaluronan; EMT, epithelial-mesenchymal transition; ALDH, aldehyde dehydrogenase; M-CSF, macrophage colony-stimulating factor; CXCR4, C-X-C chemokine receptor type 4

Fig. 3

Therapeutic approaches for targeting CSCs. The figure outlines six distinct strategies to target CSCs, including targeting CSC markers and signaling pathways, targeting CSC-associated tumor angiogenesis and metastasis, disrupting CSC niches, targeting epigenetic modifications, exploring immunotherapies, and reprogramming CSCs. VEGF, vascular endothelial growth factor; SDF-1, stromal cell-derived factor-1; HIF-1α, hypoxia-inducible factor 1-alpha; Ang-1, angiopoietin-1; TGF-β, transforming growth factor-beta; EMT, epithelial-mesenchymal transition; FAP, fibroblast activation protein; mAb, monoclonal antibody; ADC, antibody drug conjugate; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell