Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer
CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-06-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e011776.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850221146745602048 |
|---|---|
| author | Bo Yin Wei Wang Ang Li Mengjie Li Huijuan Zhou Haoran Hu Jianyi Ding Yashi Zhu Xinxin Xu Meiqin Yang Tiefeng Huang Yifan Kou Zilale Rahim Baoyou Huang Lingfei Han |
| author_facet | Bo Yin Wei Wang Ang Li Mengjie Li Huijuan Zhou Haoran Hu Jianyi Ding Yashi Zhu Xinxin Xu Meiqin Yang Tiefeng Huang Yifan Kou Zilale Rahim Baoyou Huang Lingfei Han |
| author_sort | Bo Yin |
| collection | DOAJ |
| description | CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C–C motif chemokine ligand 2)/CCR2 (C–C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC. |
| format | Article |
| id | doaj-art-a76be540dff44c03b531be6c2147ed06 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-a76be540dff44c03b531be6c2147ed062025-08-20T02:06:47ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2025-011776Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancerBo Yin0Wei Wang1Ang Li2Mengjie Li3Huijuan Zhou4Haoran Hu5Jianyi Ding6Yashi Zhu7Xinxin Xu8Meiqin Yang9Tiefeng Huang10Yifan Kou11Zilale Rahim12Baoyou Huang13Lingfei Han141 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China2 Department of Gynecology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China2 Department of Gynecology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China2 Department of Gynecology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China2 Department of Gynecology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, ChinaCKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C–C motif chemokine ligand 2)/CCR2 (C–C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC.https://jitc.bmj.com/content/13/6/e011776.full |
| spellingShingle | Bo Yin Wei Wang Ang Li Mengjie Li Huijuan Zhou Haoran Hu Jianyi Ding Yashi Zhu Xinxin Xu Meiqin Yang Tiefeng Huang Yifan Kou Zilale Rahim Baoyou Huang Lingfei Han Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer Journal for ImmunoTherapy of Cancer |
| title | Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer |
| title_full | Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer |
| title_fullStr | Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer |
| title_full_unstemmed | Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer |
| title_short | Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer |
| title_sort | inhibiting cmtm4 reverses the immunosuppressive function of myeloid derived suppressor cells and augments immunotherapy response in cervical cancer |
| url | https://jitc.bmj.com/content/13/6/e011776.full |
| work_keys_str_mv | AT boyin inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT weiwang inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT angli inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT mengjieli inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT huijuanzhou inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT haoranhu inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT jianyiding inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT yashizhu inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT xinxinxu inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT meiqinyang inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT tiefenghuang inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT yifankou inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT zilalerahim inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT baoyouhuang inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer AT lingfeihan inhibitingcmtm4reversestheimmunosuppressivefunctionofmyeloidderivedsuppressorcellsandaugmentsimmunotherapyresponseincervicalcancer |