2. Academic Validation
  3. CBX6 induces CD8+ T cell exhaustion and tumor development in esophageal squamous cell carcinoma through SMARCD1-mediated CCL8 secretion and lactate efflux

CBX6 induces CD8+ T cell exhaustion and tumor development in esophageal squamous cell carcinoma through SMARCD1-mediated CCL8 secretion and lactate efflux

  • Cell Biol Toxicol. 2025 Nov 12;41(1):150. doi: 10.1007/s10565-025-10102-x.
Lihua Wang # 1,  Guoqing Liu # 2,  Qilan Huang # 3,  Haijing Wu 4,  Xinhan Cheng 4,  Li Pan 5
Affiliations

Affiliations

  • 1 Department of Tumor Radiotherapy, Mianyang Cancer Hospital, Mianyang, 621053, Sichuan, China.
  • 2 Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • 3 Department of Neurology, Chengdu Third People's Hospital, Chengdu, 610014, Sichuan, China.
  • 4 Department of Gynecological Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, Sichuan, China.
  • 5 Department of Radiation Oncology, Sichuan Clinic Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University and Electronic Science and Technology of China, No.55, the 4th Section, Chengdu Renmin South Road, Chengdu, 610041, Sichuan, China. lipan_sch@163.com.
  • # Contributed equally.
PMID: 41219497 DOI: 10.1007/s10565-025-10102-x
Abstract

This study investigates the functions of chromobox 6 (CBX6) in esophageal squamous cell carcinoma (ESCC) and delves into its functional mechanisms. The bioinformatics insights suggested that CBX6 was overexpressed in ESCC and linked to dismal prognosis. Cbx6 knockdown was induced in mouse mEC25 cells. This procedure curbed the proliferation and migration of mEC25 cells and reduced exhaustion of the co-cultured CD8+ T cells. In vivo, Cbx6 knockdown in mEC25 cells reduced tumorigenesis while enhancing immune activity in mice. Further experiments showed that CBX6 reduced CD8+ T cell cytotoxicity by secreting C-C motif chemokine ligand 8 (CCL8) and promoting Monocarboxylate Transporter 4 (MCT4)-mediated lactate transport. Regarding the mechanism, CBX6 regulated the expression of SWI/SNF related BAF chromatin remodeling complex subunit D1 (Smarcd1) to modulate chromatin remodeling, thus promoting transcription of Ccl8 and Slc16a3 (encoding MCT4). Smarcd1 overexpression restored metabolic activity in mEC25 cells, reduced activity of co-cultured CD8+ T cells, and promoted tumorigenesis in vivo. Tissue microarrays analysis suggested that CBX6 and SMARCD1 were linked to immunosuppression and poor prognosis in clinical samples. In conclusion, this study suggests that CBX6 induces CD8+ T cell exhaustion and tumor development in ESCC through SMARCD1-mediated CCL8 secretion and lactate efflux.

Keywords

CBX6; CCL8; CD8+ T cell exhaustion; ESCC; MCT4; SMARCD1.

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