2. Academic Validation
  3. Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases

Chemotherapy triggers immune evasion by fostering LEPR+ Kupffer cell differentiation in liver metastases

  • Cancer Cell. 2026 Mar 9;44(3):658-675.e12. doi: 10.1016/j.ccell.2026.01.010.
Xuege Wang 1,  Qiang Pan 2,  Yaqi Li 3,  Ni Li 2,  Jiacheng Guo 1,  Yongqiang Gu 1,  Guoying Zhang 1,  Yannan Lian 1,  Hailong Liu 4,  Limin Cao 5,  Wei Zhang 1,  Naiheng Lin 1,  Beitao Xu 1,  Zige Jin 1,  Xin Zeng 1,  Yi Zang 1,  Xiaoyan Cheng 6,  Hui Xiao 5,  Sujun Chen 7,  Moubin Lin 8,  Guihua Wang 9,  Junjie Peng 10,  Yichuan Xiao 11,  Jun Qin 12
Affiliations

Affiliations

  • 1 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
  • 2 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Jinfeng Laboratory, Chongqing 401329, China.
  • 3 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 4 Department of General Surgery, Department of Gastroenterology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China.
  • 5 Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
  • 6 Jinfeng Laboratory, Chongqing 401329, China.
  • 7 West China School of Public Health and West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 8 Department of General Surgery, Department of Gastroenterology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China. Electronic address: [email protected].
  • 9 GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
  • 10 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 11 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. Electronic address: [email protected].
  • 12 Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].
PMID: 41687606 DOI: 10.1016/j.ccell.2026.01.010
Abstract

Conventional chemotherapy achieves clinical efficacy not only through its cytotoxic effects but also by reactivating immune surveillance. However, whether chemotherapy can inversely suppress antitumor immunity remains largely unexplored. Here, we integrate cross-species single-cell and spatial transcriptomics to investigate how chemotherapy programs immune cell plasticity. Our findings reveal that chemotherapy-educated liver-resident Kupffer cells (KCs) promote immune evasion and chemoresistance in liver metastases. These reprogrammed KCs, characterized by Leptin receptor expression (LEPR+), originate from preexisting KCs and differentiate via STING (Stimulator of interferon genes)-ID1 signaling, driven by paracrine cGAMP (cyclic GMP-AMP) released from chemotherapy-treated tumor cells. Unlike conventional KCs at the tumor periphery, LEPR+ KCs infiltrate tumors and suppress antitumor immunity through MerTK-dependent efferocytosis that eliminates chemotherapy-induced immunogenic cell death (ICD) signals. Targeting LEPR+ KCs enhances tumor immunogenicity and promotes antitumor T cell responses. Together, our study highlights the potential of combining efferocytosis inhibitors with immunotherapy to overcome chemoresistance.

Keywords

Kupffer cells; chemotherapy; efferocytosis; immune evasion; lineage plasticity; liver metastasis; paracrine cGAMP-STING signal.

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