Role of exosomal ncRNAs released by M2 macrophages in tumor progression of gastrointestinal cancers

Abstract

Macrophages (MΦs) type 2 (M2) play crucial roles in the pathogenesis of gastrointestinal cancers (GIC) by enhancing tumor progression, invasion, and metastasis. Polarized M2 has been linked to the increase of GIC tumorigenesis and drug resistance. Several studies reported that M2-derived exosomal non-coding RNAs (Exos-ncRNAs) play pivotal roles in the modulation of the GIC tumor microenvironment (TME) and mostly promote drug resistance and immunosuppression. The impact of M2-Exos-ncRNAs is attributed to altered signaling pathways, enhancement of immunoregulatory mechanisms, and post-transcriptional modulation. Recent studies described novel targets in M2-TAMs-derived Exos-ncRNAs and potential promising clinical outcomes such as inhibiting tumor formation, invasion, and metastasis. Highlighting current knowledge of M2-Exos-ncRNAs involved in GIC pathogenesis and immunomodulation would thus be a significant contribution to improving clinical outcomes. In this review, we summarize recent updates on the role of M2-TAMs-Exos-ncRNAs in GIC pathogenesis, immunosuppression, and drug resistance. A deep understanding of M2-TAMs-derived Exos-ncRNAs could help to identify potential biomarkers and therapeutic targets.

Keywords: Cancer; Immunology.

Graphical abstract

Figure 1

Role of tumor cell-derived Exos-ncRNAs and M2-TAMs-Exos-ncRNAs in the polarization of TAMs in the TME of GICs and modulation of TAM function This schematic model shows the link between Exos-ncRNAs released by tumor cells and the polarization of TAMs into M2. The figure presents the role of M2-Exos-ncRNAs in the GIC tumor progression.

Figure 2

Role of Exos-ncRNAs in the TME of GICs. Exosomal ncRNAs from M2-TAMs are released into the TME and distant organs, delivering ncRNA, which can promote tumor progression This schematic model presents the potential impact of Exos-ncRNAs released by M2-TAMs on tumor proliferation, angiogenesis, invasion, metastasis, drug resistance, and tumor immune escape.

Figure 3

Potential biological functions of Exos-ncRNAs in the TME of GICs This schematic diagram presents the impact of Exos-ncRNAs on cellular and molecular mechanisms involving GIC pathogenesis. Exos in GICs promote tumor progression and metastasis by transferring ncRNAs that enhance the expression of oncogenes and target tumor suppressor genes. They also induce onco-epigenetic modifications that induce heterogeneity and drug resistance in GIC by upregulating methylation of tumor suppressor genes and enhancing transcription of tumor proliferation genes. Furthermore, Exos-ncRNAs enhance proliferation and differentiation of immunosuppressive Tregs, and at the same time inhibit innate and adaptive anti-tumor immune responses. Exos can also transfer ncRNAs that induce CD8⁺ T cell exhaustion by inducing the upregulation of immune checkpoints such as PD-1 and TIM-3.