Modulation of tumor-derived exosomes and reprogramming of cancer-associated fibroblasts for colorectal cancer therapy

Sep 23, 2026

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Hypoxia is pervasive within the solid tumor microenvironment (TME), reshaping it through exosome release. As a key component of tumor stroma, fibroblasts govern TME remodeling and cancer progression. Targeting tumor-derived exosomes may enable novel colorectal cancer (CRC) therapies. This study shows that hypoxia-induced exosomes from CRC cells activate normal tissue-associated fibroblasts into a CAF phenotype, mediated by HIF1A-AS2 and the miR-33/HIF-1α axis, promoting angiogenesis and ECM remodeling while suppressing tumor growth when inhibited.

LanguageEnglish

CategoryResearch & Report

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Pages28

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Han et al. Molecular Cancer (2026) 25:165 Molecular Cancer [https://doi.org/10.1186/s12943-026-02661-2](https://doi.org/10.1186/s12943-026-02661-2) RESEARCH Open Access Modulation of tumor-derived exosomesand reprogramming of cancer-associated fibroblasts for colorectal cancer therapy Susu Han1*†, Tao Huang2†, Xiaoling Yin1, Ting Wang5, Qi Shi1, Yufei Tang1, Tingting Zhu1, Song Gao1*, Hua Sui3* and Fenggang Hou4,1* Abstract Hypoxia is pervasive within the solid tumor microenvironment (TME), reshaping it through exosome release. Asthe main component of the tumor stroma, fibroblasts influence TME remodeling and tumor progression. Recent advances in targeting tumor-derived exosomes offer promising opportunities for innovative colorectal cancer (CRC) therapies. Here, we found that exosomes induced by hypoxia in CRC cells (H-Exo) can promote the activation of normal tissue-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs) phenotype, with a stronger effect compared to normoxic exosomes (N-Exo) . Machine learning analysis identified HIF1A-AS2, induced by hypoxic tumor-derived exosomes, as a promising prognostic lncRNA in CRC. Pan-cancer and scRNA-seq analyses showed that high HIF1A-AS2 expression was characterized by hypoxia, angiogenesis, immunosuppression (e. g., CAFs), TGF-β, and fibroblast–CD44 interactions in CRC. HIF1A-AS2 expression progressively increased along pseudotime, shifting from early immune activation to late-stage extracellular matrix (ECM) organization, vascular niche formation, and fibroblast activation. HIF1A-AS2 in H-Exo was a key factor in the transformation of NAFs into CAFs. Exosomal HIF1A-AS2 sequesters miR-33, thereby derepressing HIF-1α, activating Notch1/ERK signaling, and upregulating angiogenic and matrix-remodeling factors (e. g., VEGF, MMP-7, and MMP-9) . Further research revealed that exosomes with silenced HIF1A-AS2 or overexpressed miR-33 could inhibit CAF infiltration, tumor cell proliferation, angiogenesis, and ECM reorganization in xenografts, ultimately suppressing tumor growth. These findings highlight that simultaneously blocking tumor exosome–driven fibroblast activation and the HIF1A-AS2/ miR-33/HIF-1α axis may serve as a promising therapeutic avenue for CRC intervention. Keywords Colorectal cancer, Hypoxia, Exosomes, HIF1A-AS2, miR-33, Cancer-associated fibroblasts, Angiogenesis †Susu Han and Tao Huang contributed equally to this work. *Correspondence: Susu Han [anyasue@163.com](anyasue@163.com) Song Gao [13111230030@fudan.edu.cn](13111230030@fudan.edu.cn)[ ](13111230030@fudan.edu.cn)Hua Sui [syh0808@163.com](syh0808@163.com)[ ](syh0808@163.com)Fenggang Hou [houfenggang@shutcm.edu.cn](houfenggang@shutcm.edu.cn) 1Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China 2The Affiliated Hospital of Ningbo University, Ningbo, China 3Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201803, China 4Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China 5Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the

FAQs

How does hypoxia affect exosome release in colorectal cancer?

Hypoxia in the tumor microenvironment drives CRC cells to release exosomes that can reshape stromal cell states. These hypoxia-derived exosomes promote fibroblast reprogramming toward a cancer-associated phenotype.

What role does HIF1A-AS2 play in fibroblast activation?

HIF1A-AS2 induced by hypoxic tumor-derived exosomes is identified as a prognostic lncRNA in CRC. It contributes to transformation of NAFs into CAFs through downstream signaling.

How does exosomal HIF1A-AS2 regulate the miR-33/HIF-1α pathway?

Exosomal HIF1A-AS2 sequesters miR-33, derepressing HIF-1α. This activation triggers Notch1/ERK signaling and increases angiogenic and matrix-remodeling factors.

Sep 23, 2026

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