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  3. Radiotherapy disrupts ferroptosis tolerance by reducing DNMT1 levels and uncouples STING silencing in LKB1-deficient lung tumors

Radiotherapy disrupts ferroptosis tolerance by reducing DNMT1 levels and uncouples STING silencing in LKB1-deficient lung tumors

  • Free Radic Biol Med. 2026 May:248:150-161. doi: 10.1016/j.freeradbiomed.2026.02.052.
Yan-Pei Zhang 1,  Fei-Fei Wu 2,  Ze-Nan Wu 2,  Yan Li 3,  Jia-Qi Chen 2,  Xiao-Ting Cai 2,  Xin-Yi Quan 2,  Zi-Xuan Rong 2,  Ze-Qin Guo 2,  Zhi-Jiao Duan 4,  Zhong-Yi Dong 5,  Lan-Ying Gou 6,  Da-Yong Zheng 7,  De-Hua Wu 8
Affiliations

Affiliations

  • 1 Department of Oncology, The Eighth Affiliated Hospital of Southern Medical University (The First People's Hospital of Shunde District Foshan City), Shunde, 528333, China.
  • 2 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Radiology, Xianyang Hospital, Yan'an University, Xianyang, 712000, China.
  • 4 Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 5 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 6 Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 7 Department of Oncology, The Eighth Affiliated Hospital of Southern Medical University (The First People's Hospital of Shunde District Foshan City), Shunde, 528333, China. Electronic address: [email protected].
  • 8 Department of Oncology, The Eighth Affiliated Hospital of Southern Medical University (The First People's Hospital of Shunde District Foshan City), Shunde, 528333, China; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
PMID: 41722660 DOI: 10.1016/j.freeradbiomed.2026.02.052
Abstract

Liver kinase B1 (LKB1) deficiency confers primary resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer; however, the underlying mechanisms remain unclear. Through single-cell RNA Sequencing analysis of a genetically engineered KrasG12D/+-driven mouse model with a conditional Lkb1 knockout, we discovered that LKB1-deficient tumors display dysregulation of the Ferroptosis pathway. Analyses of multiple clinical cohorts revealed that LKB1-deficient lung tumors exhibit elevated Ferroptosis resistance scores, which contribute to immunotherapy failure. Subsequent in vitro and in vivo experiments have shown that the deficiency of LKB1 hinders cellular susceptibility to Ferroptosis induction, a situation that can be rectified by radiotherapy through DNMT1-dependent OSGIN1 downregulation. Concurrently, radiotherapy leads to the revival of stimulator of interferon genes (STING) expression, thereby triggering the activation of the immune microenvironment in LKB1-deficient lung tumors. The combination of radiotherapy with anti-PD-1 antibodies represents an effective, tailored therapeutic strategy in an LKB1-deficient murine model, resulting in significant tumor suppression through a ferroptosis-dependent mechanism. Collectively, the findings demonstrate that LKB1 deficiency promotes Ferroptosis resistance in lung Cancer cells. Radiotherapy simultaneously disrupts Ferroptosis tolerance through the DNMT1-OSGIN1 axis and activates the STING pathway, effectively reversing ICI resistance in LKB1-deficient lung tumors.

Keywords

Ferroptosis; Immune checkpoint inhibitors; LKB1 mutation; Non-small cell lung cancer; Radiotherapy.

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