Designed peptide disrupts UEIS-TBK1 condensation, reducing tumor growth and boosting ICB response in macrophages

Despite the success of immune checkpoint blockade (ICB) in cancer treatment, enhancing its efficacy remains a significant challenge. A critical barrier is the immunosuppressive tumor microenvironment, often driven by tumor-associated macrophages (TAMs). These macrophages can adopt a protumorigenic phenotype, inhibiting effective antitumor T cell immunity. Understanding and targeting novel pathways that regulate TAM function, particularly those involved in cGAS-STING-type I interferon (IFN) signaling, could unlock new strategies to overcome ICB resistance and improve patient outcomes.

Researchers identified an immunoregulatory micropeptide, UEIS (USP30-AS1-encoded immune suppressor), encoded by the long noncoding RNA USP30-AS1 gene, which is highly expressed in tumor-associated macrophages. They investigated its role in driving macrophages toward a protumorigenic phenotype and inhibiting antitumor T cell immunity. Mechanistic studies involved analyzing UEIS induction by cGAS-STING-type I IFN signaling and its interaction with key signaling molecules. They then designed a peptide to disrupt the identified UEIS-TBK1 condensation, testing its ability to inhibit UEIS function in tumor-associated macrophages and its impact on tumor growth and response to immune checkpoint blockade in relevant tumor models.

The study identified UEIS as a micropeptide highly expressed in tumor-associated macrophages that actively drives them toward a protumorigenic phenotype, thereby inhibiting antitumor T cell immunity. Mechanistically, UEIS is induced in macrophages by cGAS-STING-type I IFN signaling at a relatively late stage following tumoral DNA stimulation. It exerts a negative feedback regulation on type I IFN signaling by forming biomolecular condensates with TBK1, which inhibits TBK1's 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 designed peptide specifically engineered to disrupt UEIS-TBK1 condensation successfully inhibited UEIS function in tumor-associated macrophages, leading to reduced tumor growth and an increased response to immune checkpoint blockade.