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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Je-Jung Lee,
  • Woo Joong Rhee,
  • So Young Kim,
  • Jisun Lee,
  • Su Ful Jung,
  • Jooyeon Oh,
  • In Ho Park,
  • Jeon-Soo Shin

摘要

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.