Table 2.

Regulatory mechanism of EV cargoes in the development of immune suppression in CRC

EV cargo	Producing cells	Expression patterns	Target cells	Related genes and/or pathways	Function/outcome	References
Non-coding RNAs
miR-1246	mutp53 CRC cells	Increased	Primary monocytes	NA	Macrophage reprogramming into tumor-promoting phenotype with increased TGF-β secretion	[103]
miR-155-5p	M2 macrophage	Increased	Colon cancer cells	Inhibition of ZC3H12B expression and upregulation of IL-6; escalates CD3 + T cell proliferation and the proportion of IFN-γ + T cells	Increased cancer cell proliferation and antiapoptosis ability; abrogates T cell immune response and promotes tumor formation	[104]
miR-424	Human CRC cell lines; mouse CRC cell lines	Increased	Tumor-infiltrating T cells and DCs	Diminishes CD28-CD80/86 costimulatory pathway	Resistance to immune checkpoint blockade immunotherapy; dampens T cell antitumor response	[108]
miR-21-5p and miR-200a	human CRC cells; murine colon cancer cells	Increased	Human monocyte cell line	Induces M2 polarization and PD‐L1 expression in macrophages through regulation of PTEN/AKT and SCOC1/STAT1 pathways	M2 macrophage polarization; suppresses CD8 + T cell activity and enhances tumor growth	[109]
miR-146a-5p	CRC stem cells	Increased	CRC cells	attenuates Numb expression; increased tumor-infiltrating CD66b + neutrophils and decreased number of CD8 + T cells	Increased stem-like properties and tumorigenesis; establishes immunosuppressive TME	[110]
miR-4780	N2-like neutrophils	Increased	CRC cells	Targets SOX11 expressions	Increased viability, migration, and invasion; promotes EMT and angiogenesis	[111]
miR-10b	CRC cell line; tissue specimens from CRC patients	Increased	Human fibroblasts	Augments TGF-β and SM α-actin expression by suppressing PIK3CA expression and PI3K/Akt/mTOR pathway	Promotes fibroblast activation and tumor growth	[118]
Proteins
TGF-β1	colon cancer cells	Increased	Human T-cell leukemia Jurkat cells, PBMCs, and CD4 + T cells	Triggers TGF-β/Smad signaling and diminishes SAPK signaling	Inhibition of T cell proliferation; transforms T cells into Treg-like phenotype; increased tumor growth	[105]
TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand	CRC cell lines; blood sample of CRC patients	Increased	CD8 + T cells from CRC patients	Fas ligand and TRAIL	Induction of apoptosis in CD8 + T cells in vivo and in vitro	[106]
PD-L1	Cancer cell lines	Increased	T cells	PD1/PD-L1 pathway	Inhibition of T cell activity in lymph nodes; increased tumor growth	[107]
S100A9	Granulocytic MDSCs (G-MDSCs)	Increased	CT‐26 colon cancer cells	Activation of NF‐κB and STAT3 signaling	Increased stemness and growth in tumor-bearing mice; increased susceptibility to colitis‐associated colon cancer in mice; enhanced recruitment of MDSCs	[120]
Other cargoes
Triphosphate RNAs	Murine CRC stem cells	Increased	Bone marrow-derived neutrophils	Upregulates NF-κB signaling and induces IL-1β expression	Extends neutrophil survival in the bone marrow; induction of a pro-tumoral phenotype in neutrophils; increased tumorigenicity	[112]
Tumor-derived EVs	CRC cell lines; melanoma cell lines	NA	CD14 + monocytes	Downregulation of CD80 and CD86 costimulatory molecules and HLA class II expression	Hinders CD14 + monocytes differentiation into DCs; increased TGF-B-secreting monocytes with suppressive activity on T cells	[119]