G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition

Sep 24, 2026

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Granulocytic myeloid-derived suppressor cells (G-MDSCs) and their exosomes shape how monocytic MDSCs (M-MDSCs) differentiate into M2 macrophages, thereby driving colitis-associated cancer progression. The study investigates cross-talk and underlying mechanisms using immunofluorescence, FACS, immunoblotting, siRNA, and antibodies, including IL-6 antibody treatment and STAT3 inhibition in dextran sulfate sodium-induced colitis-to-cancer mice. Results show IL-6–mediated enrichment of exosomal miR-93–5p downregulates STAT3 activity, enhancing anti-STAT3 effects. Overall, combining STAT3 inhibition with strategies blocking IL-6–driven miR-93–5p production supports CAC prevention and treatment.

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CategoryHealthcare

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What Is Already Known on This Topic

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Open access Original research G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition Yungang Wang ,1 Hongli Liu,2 Zhe Zhang,1 Dezhi Bian,1 Keke Shao,1 Shengjun Wang,3 Yanxia Ding 1 To cite: Wang Y, Liu H, Zhang Z, et al. G-MDSCderived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition. Journal for ImmunoTherapy of Cancer 2023;11:e006166 . doi:10.1136/jitc-2022-006166 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2022-006166) . YW and HL contributed equally. Accepted 25 January 2023 © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Yanxia Ding; [wzidyx2010@163.com](wzidyx2010@163.com) Yungang Wang; [wyg1223@126.com](wyg1223@126.com) Dr Shengjun Wang; [sjwjs@ujs.edu.cn](sjwjs@ujs.edu.cn) ABSTRACT Backgrounds In inflammatory bowel disease microenvironment, transdifferentiation of myeloidderived suppressor cells (MDSCs) and M2 macrophage accumulation are crucial for the transition of colitis-tocancer. New insights into the cross-talk and the underling mechanism between MDSCs and M2 macrophage during colitis-to-cancer transition are opening new avenues for colitis-associated cancer (CAC) prevention and treatment. Methods The role and underlying mechanism that granulocytic MDSCs (G-MDSCs) or exosomes (Exo) regulates the differentiation of monocytic MDSCs (M-MDSCs) into M2 macrophages were investigated using immunoﬂuorescence, FACS, IB analysis, etc, and employing siRNA and antibodies. In vivo efficacy and mechanistic studies were conducted with dextran sulfate sodium-induced CAC mice, employed IL-6 Abs and STAT3 inhibitor. Results G-MDSCs promote the differentiation of M-MDSC into M2 macrophages through exosomal miR-93–5 p which downregulating STAT3 activity in MMDSC. IL-6 is responsible for miR-93–5 p enrichment in G-MDSC exosomes (GM-Exo) . Mechanistically, chronic inflammation-driven IL-6 promote the synthesis of miR- 93–5 p in G-MDSC via IL-6R/JAK/STAT3 pathway. Early use of IL-6 Abs enhances the effect of STAT3 inhibitor against CAC. Conclusions IL-6-driven secretion of G-MDSC exosomal miR-93–5 p promotes the differentiation of M-MDSC into M2 macrophages and involves a STAT3 signaling mechanism that promote colitis-to-cancer transition. Combining STAT3 inhibitors with strategies that inhibit IL- 6-mediated G-MDSC exosomal miR-93–5 p production is beneficial for the prevention and treatment of CAC. INTRODUCTION Colitis-associated cancer (CAC) does not display the adenoma-carcinoma sequence which is typical for sporadic colorectal cancer (CRC) . Chronic inflammation and the increased turnover of epithelial cells contribute to the development of low-grade and high-grade dysplasia, which may further transform into CAC.1–3 Inflammatory bowel WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Myeloid-derived suppressor cells (MDSCs) and M2 macrophages accumulate under inflammatory bowel disease and colitis-associated cancer (CAC) conditions, but the interaction between them, as well as the role in regulating the transition of colitis-tocancer are unclear.
WHAT THIS STUDY ADDS | | --- | | ⇒ Here, we report that granulocytic MDSCs (G-MDSCs) promote the differentiation of monocytic MDSC (MMDSC) into M2 macrophages through releasing exosomal miR-93–5 p. IL-6 is responsible for miR- 93–5 p enrichment in G-MDSC exosomes.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY | ⇒ These findings are the first to demonstrate that GMDSCs promote the differentiation of M-MDSC into M2 macrophages, thereby facilitating colitis-tocancer transition. Blocking the crosstalk between MDSCs and M2 is beneficial for the preve

FAQs

What cellular transition is investigated in this study?

The study examines how G-MDSC-derived exosomes promote the differentiation of M-MDSCs into M2 macrophages during colitis-to-cancer transition.

Which molecular pathway links IL-6 to the exosomal miRNA mechanism?

Chronic inflammation-driven IL-6 promotes synthesis of miR-93–5p in G-MDSCs via the IL-6R/JAK/STAT3 pathway, leading to miR-93–5p enrichment in G-MDSC exosomes.

How do IL-6 blockade and STAT3 inhibition interact for CAC?

Early use of IL-6 antibodies enhances the effect of STAT3 inhibitor against colitis-associated cancer.

Sep 24, 2026

Uploaded by Angel