Exosomes as double-edged swords: Bridging inflammation and cancer through molecular communication and therapeutic potential

This review is led by Professor Xi Peng (Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University). Exosomes, lipid bilayer nanovesicles secreted by nearly all cell types, function as crucial mediators of intercellular communication by transferring proteins, nucleic acids, and lipids. The review emphasizes their context-dependent functions in inflammation, where they can exhibit both pro-inflammatory and anti-inflammatory effects. In acute inflammation, such as sepsis, exosomes can promote inflammatory responses by delivering cytokines (e.g., IL-1β, TNF-α), chemokines (e.g., CXCL2), and pro-inflammatory miRNAs (e.g., miR-27-3p, miR-221) that activate immune cells like macrophages and neutrophils, exacerbating tissue damage. Conversely, in chronic inflammation, exemplified by inflammatory bowel disease (IBD), exosomes often suppress excessive immune responses. Mesenchymal stem cell (MSC)-derived exosomes, carrying anti-inflammatory molecules like TGF-β, IL-10, and miRNAs such as miR-146a and miR-181a, can mitigate inflammation by modulating immune cell activity (e.g., promoting Treg cells, inhibiting M1 macrophage polarization), repairing intestinal barrier function, and influencing gut microbiota composition. Exosomes also significantly shape the inflammatory microenvironment (IME) by regulating the balance and function of key cells (macrophages, dendritic cells, T cells) and the expression of pro-inflammatory enzymes (e.g., COX-2, iNOS).

In the context of cancer, exosomes play pivotal roles in remodeling the tumor microenvironment (TME), facilitating tumor progression, metastasis, and immune evasion. Tumor-derived and stromal cell-derived exosomes orchestrate TME dynamics by interacting with cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), the extracellular matrix (ECM), and blood vessels. Their cargo—including proteins (e.g., MMPs, VEGF, PD-L1), lipids, and functional RNAs (miRNAs, lncRNAs)—drives critical processes. Exosomes promote angiogenesis (e.g., via VEGF), degrade the ECM to enable invasion, induce epithelial-mesenchymal transition (EMT) (e.g., via TGF-β, SNAI1), and activate CAFs into a tumor-promoting state. Crucially, they facilitate immune escape by carrying immunosuppressive molecules like PD-L1 and LGALS9, which inhibit T cell activity and dendritic cell function, or by polarizing TAMs towards an immunosuppressive M2 phenotype (e.g., via miR-21-5p). Furthermore, exosomes contribute to the transition from chronic inflammation to cancer by transporting oncogenic and inflammatory molecules that impact relevant signaling pathways (e.g., NF-κB). They also mediate drug resistance by transferring resistance-conferring miRNAs between cells.

The review underscores the diagnostic potential of tumor-derived exosomes, which serve as non-invasive biomarkers correlating with disease progression. Clinically, exosomes show promise as therapeutic agents themselves (e.g., MSC-exosomes for anti-inflammatory effects) and as drug delivery vehicles, with ongoing clinical trials exploring these applications for both inflammatory diseases and cancers. However, significant challenges hinder clinical translation, including the need for standardized isolation methods, scalable production techniques, and a deeper understanding of exosome functional heterogeneity and cargo-specific mechanisms. Future research priorities include elucidating these mechanisms, optimizing engineering strategies for therapeutic exosomes, and advancing personalized exosome-based therapies. The authors conclude that by bridging molecular insights with clinical applications, exosomes hold substantial potential for advancing precision medicine in inflammation and oncology.

See the article:

 Exosomes in inflammation and cancer: from bench to bedside applications. 

https://doi.org/10.1186/s43556-025-00280-9