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

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.