Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment

Abstract

Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.

Keywords: cancer stem cells; exosomes; extracellular vesicles; immune cells; tumor microenvironment.

Figure 1

Overview of cancer stem cells (CSCs). This illustration delineates the fundamental characteristics of CSCs, encompassing their resilience against standard anti-cancer treatments. CSCs possess a remarkable ability for self-renewal, ensuring the perpetuation of the cancer cell population. CSCs are also capable of multi-lineage differentiation, which contributes to the cellular complexity and heterogeneity of tumors. Furthermore, CSCs are often implicated in tumor relapse due to their ability to remain dormant and then re-initiate tumor growth. Lastly, their role in metastasis is underscored by their potential to disseminate and form new tumors at distant sites, which is a hallmark of advanced cancer stages. These CSC characteristics are critical for understanding tumor behavior and developing targeted therapeutic strategies.

Figure 2

Extracellular vesicles (EVs). EVs encapsulate a diverse array of bioactive molecules, including surface proteins, cytosolic proteins, nucleic acids (both DNA and RNA), metabolites, lipids, and peptides. EVs are classified into exosomes and microvesicles based on origin of formation and their size.

Figure 3

Crosstalk between CSCs and immune cells through EVs within tumor microenvironment (TME). (A) TME composition. The tumor ecosystem encompasses a diversity of cell types including cancer cells, CSCs, immune cells, and non-cellular component like extracellular matrix and blood vessels, all of which are integral to TME. (B) The effect of EVs on CSCs and immune cells. These EVs transport biological signals that prime immune cells to undergo various functional alterations such as immunosuppressive phenotype acquisition, cytotoxicity inhibition and DC activation, and in turn, immune cells exert certain influence on CSCs such as promotion of growth and metastasis. CSC, cancer stem cell. NETs, neutrophil extracellular traps. DC, dendritic cell. MDSC, myeloid-derived suppressor cell. Some elements in Figures 1 – 3 were created with BioRender.com.