Tumour-associated high endothelial venules drive portal-specific immune evasion in lymph nodes via ALOX12
High endothelial venules (HEVs) provide another portal for tumour metastasis. However, whether HEVs and other blood vessels exert different effects on tumour escape remains unknown. Here we show that tumour involvement in HEVs is an independent prognostic marker for patients with lymph node (LN)-positive female breast cancer. Tumour cells that spread via HEVs are less immunogenic and more capable of establishing distant metastases than those that spread through non-HEV blood vessels. Mechanistically, the expression of arachidonate 12-lipoxygenase (ALOX12) in HEVs is promoted by tumour-derived semaphorin 3 C (SEMA3C). Reciprocally, ALOX12-derived metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) promotes ADAR1 p150-dsRNA phase separation in tumour cells by selectively binding to ADAR1 p150. Consequently, the immune recognition of dsRNA is reduced because of the increased adenosine-to-inosine (A-to-I) RNA editing in tumour cells. Collectively, our data indicate that a unique lymphatic anatomical structure mediates specific immune evasion of migrating tumour cells.
Authors
- Dong‐Ming Kuang (ORCID: https://orcid.org/0000-0003-3570-9717)
- Shicheng Su (ORCID: https://orcid.org/0000-0003-2280-3587)
- Zhen Lin (ORCID: https://orcid.org/0000-0001-5785-1496)
- Boxuan Zhou (ORCID: https://orcid.org/0000-0002-1103-0059)
- Jin Jin (ORCID: https://orcid.org/0000-0002-0798-5696)
- Yunjie Zeng (ORCID: https://orcid.org/0000-0003-3815-0461)
- Jiang Li
- Xiaoqi Weng
- Lijuan Bian
- Shunrong Li
- Shubin Yu
- Yu Shi (ORCID: https://orcid.org/0009-0007-4117-9579)
- Shijian Song
- Nu Zhang (ORCID: https://orcid.org/0000-0002-2817-7065)
- Yiqing Zheng (ORCID: https://orcid.org/0000-0002-1600-8539)
- Jinting Liu
- Xinwei Liu (ORCID: https://orcid.org/0000-0002-2860-9542)
- Jian-You Liao (ORCID: https://orcid.org/0000-0002-5586-3458)
- Qionglan Tang
- Shouping Xu (ORCID: https://orcid.org/0000-0001-6154-3381)
- Jiayao Pan
- Qidong Xia (ORCID: https://orcid.org/0009-0003-7585-6989)
- Jiaqian Li
Institutions
- Guiyang Medical University (CN)
- Army Medical University (CN)
- Harbin Medical University (CN)
- Sun Yat-sen University (CN)
- Sun Yat-sen Memorial Hospital (CN)
- Third Affiliated Hospital of Harbin Medical University (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Southwest Hospital (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-11
- DOI
- https://doi.org/10.1038/s41467-026-72412-w
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00