Targeting CTLA-4 in cancer cells induces senescence via DNA-PKcs-STING-AKT axis

Abstract Immune checkpoints such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4), PD-1, and PD-L1 have been targeted for cancer therapy. However, the efficacy of this treatment approach remains limited. Beyond its expression on the T-cell surface, CTLA-4 is also expressed in various cancer cells and plays roles in cell proliferation, metastasis, and apoptosis. Here, we reveal that targeting CTLA-4 in melanoma cells leads to genomic instability and DNA-PKcs-STING-AKT pathway activation (via p53 and p21), which in turn blocks cell proliferation and induced senescence. Notably, DNA-PKcs orchestrates CTLA-4-depletion-induced senescence via the STING pathway regulation. To the best of our knowledge, this is the first study to report CTLA-4 leads senescence via micronuclei induction, which triggers DNA-PKcs and eventually suppresses cancer growth. These findings provide a better understanding of the mechanisms underlying CTLA-4 targeting-cancer therapy and future treatment strategies.