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  3. HMOX1 expression influence the role of macrophage in EGFR-TKI resistance of lung adenocarcinoma

HMOX1 expression influence the role of macrophage in EGFR-TKI resistance of lung adenocarcinoma

  • Int Immunopharmacol. 2026 Jan 1;168(Pt 1):115795. doi: 10.1016/j.intimp.2025.115795.
Hongkun Fang 1,  Hao Wang 2,  Xinyue Liu 2,  Yi Deng 3,  Lishu Zhao 2,  Kandi Xu 2,  Li Ye 2,  Yujin Liu 2,  Wencheng Zhao 2,  Ying Zhou 4,  Qiyuan Li 5,  Yayi He 6
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, People's Republic of China; Shandong ProvincialKey Medical and Health Laboratory of BT and IT for Thoracic Oncology (The First Affiliated Hospital of Shandong Second Medical University), Weifang, Shandong 261041, People's Republic of China.
  • 2 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, People's Republic of China; School of Medicine, Tongji University, No 1239 Siping Road, Shanghai 200433, People's Republic of China.
  • 3 Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
  • 4 National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, 361102, People's Republic of China. Electronic address: yingzhou@xmu.edu.cn.
  • 5 National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, 361102, People's Republic of China; Department of hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, People's Republic of China; Department of Pediatrics, The First Affiliated Hospital of Xiamen University, School of medicine, Xiamen 361102, People's Republic of China. Electronic address: qiyuan.li@xmu.edu.cn.
  • 6 Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, People's Republic of China; School of Medicine, Tongji University, No 1239 Siping Road, Shanghai 200433, People's Republic of China. Electronic address: yayi.he@tongji.edu.cn.
PMID: 41205382 DOI: 10.1016/j.intimp.2025.115795
Abstract

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the first-line therapy for lung adenocarcinoma (LUAD) patients having EGFR-sensitive mutations. Although it has significantly prolonged survival of patients, resistance to EGFR-TKI treatment can not be avoided. While many intrinsic factors related to resistance have been identified, little is known about the role of non-tumor cells, particularly macrophages in the tumor microenvironment (TME), in TKI resistance. In the current study, we performed scRNA-seq analysis on 7458 cells from 12 patients with EGFR-TKI sensitive or resistant tumors to investigate the differential tumor microenvironment in these tumors. We identified significant differences in the immune cell fractions that presented between EGFR-TKI sensitive and resistant tumors, with lymphocytes being the predominant immune cells in EGFR-TKI resistant tumors, while myeloid cells were more prominent in EGFR-TKI sensitive tumors. We identified HMOX1hi macrophages, exhibiting an anti-inflammatory M2 polarization, are more abundant in EGFR-TKI resistant tumors than in EGFR-TKI sensitive tumors. We further revealed extensive communication between macrophages and CAM-related tumor cells through SPP1 and FN1 signaling. The findings suggested that manipulating HMOX1 expression in macrophages might change their function and modulate sensitivity of patients to EGFR-TKI.

Keywords

Drug resistance; EGFR-TKI; Lung adenocarcinoma; Macrophage; Single cell sequencing.

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