DNA-PKcs orchestrates CTLA-4 depletion-induced senescence in cancer cells.

Immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have been targeted in cancer therapy, however, the efficacy of these interventions remains limited. Beyond its immune function on T cell surfaces, CTLA-4 is also expressed in various intrinsic cancer cells, where it influences cell proliferation, metastasis, and apoptosis. The present study aimed to investigate the function of CTLA-4 in cancer cells by investigating the consequences of CTLA-4 depletion in melanoma cells. We found that targeting CTLA-4 in melanoma cells inhibited proliferation via the induction of senescence, which was attributed to genomic instability resulting from a decrease in Aurora B expression, leading to the activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-stimulator of interferon genes (STING) pathway. Notably, DNA-PKcs coordinates CTLA-4 depletion-induced senescence by regulating the STING pathway. Mouse study showed that the tumor suppressive effect of CTLA-4 depletion in allograft cancer models via senescence induction. Furthermore, public data analysis showed a negative correlation between CTLA-4 and DNA-PKcs expressions in patients. Conclusively, CTLA-4-depletion induces senescence via genome instability, which activates DNA-PKcs and ultimately leads to cancer growth regression. These findings suggest that intracellular CTLA-4 targeting can confer to cancer therapy. CTLA-4 depletion-induced senescence in cancer. CTLA-4 depletion-induced senescence in cancer. CTLA-4 deficiency induces senescence via the DNA PKcs-STING-AKT pathway in cancer cells. When CTLA-4 is depleted in cancer cells, the genome becomes unstable due to the reduction of Aurora B expression, then consequently DNA damage occurs accompanied by micronuclei formation in the cytosol. Subsequently, DNA-PKcs is activated and sequentially promotes the STING-AKT-p21 signaling pathway, which mediates cellular senescence and eventually prevents tumor growth.