A micropeptide encoded by the lncRNA USP30-AS1 promotes tumor growth by attenuating cGAS-STING-type I IFN signaling in macrophages.

Authors

Xingwen Wang, Yi Zhang, Jiangwen Ma, Qingyu Lin, Zhenghang Wang, Guixue Hou, Yutong Wei, Minqiao Lu, Meiqi Wang, Tianyu Li, Shanliang Zheng, Wenxin Zhang, Yafan Gong, Tianqi Guan, Hao Liu, Xiaotian Zhang, Li Li, Ying Hu

Published in

Nature cancer. Jul 09, 2026. Epub Jul 09, 2026.

Abstract

Immune checkpoint blockade has achieved remarkable success in cancer treatment; however, enhancing its efficacy remains a challenge. Here we identified an immunoregulatory micropeptide encoded by the long noncoding RNA USP30-AS1 gene, highly expressed in tumor-associated macrophages. The so-designated UEIS (USP30-AS1-encoded immune suppressor) drives macrophages toward a protumorigenic phenotype, thereby inhibiting antitumor T cell immunity. Mechanistically, UEIS is induced in macrophages by cGAS-STING-type I interferon signaling at a relatively late stage following tumoral DNA stimulation, and exerts a negative feedback regulation on the type I interferon signaling by forming biomolecular condensates with TBK1, thereby inhibiting its interaction with STING. Both an intrinsically disordered region and an alpha helix at the extreme N terminus of UEIS were essential for its function. A peptide designed to disrupt UEIS-TBK1 condensation successfully inhibited UEIS function in tumor-associated macrophages, leading to reduced tumor growth and increased response to immune checkpoint blockade. Thus, these findings highlight UEIS as a promising therapeutic target for cancer treatment.

PMID:
42426285
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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