2. Academic Validation
  3. Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer

Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer

  • Cell Rep Med. 2025 Dec 18:102529. doi: 10.1016/j.xcrm.2025.102529.
Yong Xi 1,  Zhijie Zhao 2,  Yundong Zhou 3,  Chengliang Yin 4,  Yuxin Li 5,  Xiao Xu 6,  Wenyi Jin 7,  Chengbin Lin 8,  Kui Zhao 9,  Junjie Kuang 10,  Senlian Hong 11,  Bentong Yu 12,  João Conde 13,  Shiyuan Liu 14,  Weiyu Shen 15
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China.
  • 2 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 3 Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China; The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
  • 4 Department of Biomedical Engineering, Faculty of Engineering, Universiti Malaya, Kuala Lumpur, Malaysia.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 6 Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 7 Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan University, Wuchang, Wuhan 430060, China; Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong SAR 999077, China.
  • 8 Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China.
  • 9 School of Nursing, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China.
  • 10 Department of Oncology, Liuzhou People's Hospital, Guangxi Medical University, No. 8, Wenchang Road, Chengzhong District, Liuzhou, Guangxi, China.
  • 11 State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 12 Department of Thoracic Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China. Electronic address: [email protected].
  • 13 Comprehensive Health Research Centre (CHRC), NOVA Medical School, Faculdade de Ciências Médicas, NMS
  • 14 Electronic address: [email protected].
  • 15 Department of Thoracic Surgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China. Electronic address: [email protected].
  • 16 Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China. Electronic address: [email protected].
PMID: 41418775 DOI: 10.1016/j.xcrm.2025.102529
Abstract

This study explores the role of efferocytosis in esophageal squamous cell carcinoma (ESCC) using single-cell RNA Sequencing and in vitro/in vivo assays. Analyzing 27 samples from 9 patients with ESCC, we identify diverse cell types and significant heterogeneity in the tumor microenvironment, with a focus on efferocytosis. Our findings highlight that macrophages engulf apoptotic tumor cells, thereby impairing immune responses and promoting tumor progression. Notably, TP63 and RAC2 emerge as key regulators of this process, influencing efferocytosis and immune modulation. Functional assays demonstrate that disrupting these pathways alters macrophage efferocytosis and impacts tumor growth in vivo. These results suggest that targeting efferocytosis pathways offers potential therapeutic strategies for ESCC, enhancing antitumor immunity and improving patient outcomes. The study underscores the complex interactions between tumor cells and the immune system, with efferocytosis representing a promising therapeutic target.

Keywords

TP63/RAC2 axis; apoptotic tumor cells; cancer immunotherapy; efferocytosis; esophageal cancer; immune suppression; macrophage polarization; single-cell RNA sequencing; tumor microenvironment; tumor-associated macrophages.

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