2. Academic Validation
  3. Interleukin-33 (IL-33) promotes DNA damage-resistance in lung cancer

Interleukin-33 (IL-33) promotes DNA damage-resistance in lung cancer

  • Cell Death Dis. 2025 Apr 11;16(1):274. doi: 10.1038/s41419-025-07624-x.
Haoge Luo 1,  Liping Liu 1,  Xiaoping Liu 2,  Yingdong Xie 1,  Xin Huang 3,  Ming Yang 4 5,  Chen Shao 6 7,  Dong Li 8 9
Affiliations

Affiliations

  • 1 Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 2 Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 3 Department of Microbiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 4 Department of Biochemistry & Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China.
  • 5 Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
  • 6 Department of Biochemistry & Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, China. shaochen@jlu.edu.cn.
  • 7 Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China. shaochen@jlu.edu.cn.
  • 8 Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China. lidong1@jlu.edu.cn.
  • 9 Medical Basic Research Innovation Center of Airway Disease in North China, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China. lidong1@jlu.edu.cn.
PMID: 40216748 DOI: 10.1038/s41419-025-07624-x
Abstract

Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during Cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant Cancer cells.

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