2. Academic Validation
  3. Inhibition of MBTPS1 enhances antitumor immunity and potentiates anti-PD-1 immunotherapy

Inhibition of MBTPS1 enhances antitumor immunity and potentiates anti-PD-1 immunotherapy

  • Nat Commun. 2025 Apr 30;16(1):4047. doi: 10.1038/s41467-025-59193-4.
Yi-Yu Wang # 1,  Jin-Fei Lin # 1 2,  Wen-Wei Wu # 1,  Zhe Fu # 1,  Fen Cao 3,  Yan-Xing Chen 1,  Hai-Yu Mo 1,  Hui Sheng 1,  Ze-Xian Liu 1,  Zhao-Lei Zeng 1,  Xin-Yuan Guan 4,  Huai-Qiang Ju 5 6,  Kun Liao 7,  Rui-Hua Xu 8 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, P. R. China.
  • 2 Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, P. R. China.
  • 4 Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, P. R. China.
  • 5 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, P. R. China. juhq@sysucc.org.cn.
  • 6 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, P. R. China. juhq@sysucc.org.cn.
  • 7 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, P. R. China. liaokun@sysucc.org.cn.
  • 8 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, 510060, P. R. China. xurh@sysucc.org.cn.
  • 9 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, P. R. China. xurh@sysucc.org.cn.
  • # Contributed equally.
PMID: 40307212 DOI: 10.1038/s41467-025-59193-4
Abstract

Despite advances in Cancer Immunotherapy, colorectal Cancer patients exhibit limited therapeutic responses. Therefore, the exploration of strategies combining immunotherapy with Adjuvant approaches to enhance adaptive immune responses is in demand. Here, we perform a customized in vivo CRISPR-Cas9 screen to target genes encoding membrane and secreted proteins in CRC mouse models with different immune characteristics. We observe that loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells enhances antitumor immunity and potentiates anti-PD-1 therapy. Mechanistic studies reveal that tumor cell-intrinsic MBTPS1 competes with USP13 for binding to STAT1, thereby disrupting the USP13-dependent deubiquitination-mediated STAT1 stabilization. The upregulated STAT1-transcribed chemokines including CXCL9, CXCL10, and CXCL11, promote CXCR3+CD8+ T cell infiltration. Notably, the regulatory role of MBTPS1 in antitumor immunity operates independently of its classic function in cleaving membrane-bound transcription factors. Collectively, our results provide a theoretical basis for MBTPS1 as a potential immunotherapy target.

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