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

Yi-Yu Wang, Jin-Fei Lin, Wen-Wei Wu, Zhe Fu, Fen Cao, Yan-Xing Chen, Hai-Yu Mo, Hui Sheng, Ze-Xian Liu, Zhao-Lei Zeng, Xin-Yuan Guan, Huai-Qiang Ju (), Kun Liao () and Rui-Hua Xu ()
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Yi-Yu Wang: Sun Yat-sen University
Jin-Fei Lin: Sun Yat-sen University
Wen-Wei Wu: Sun Yat-sen University
Zhe Fu: Sun Yat-sen University
Fen Cao: Sun Yat-sen University
Yan-Xing Chen: Sun Yat-sen University
Hai-Yu Mo: Sun Yat-sen University
Hui Sheng: Sun Yat-sen University
Ze-Xian Liu: Sun Yat-sen University
Zhao-Lei Zeng: Sun Yat-sen University
Xin-Yuan Guan: The University of Hong Kong-Shenzhen Hospital
Huai-Qiang Ju: Sun Yat-sen University
Kun Liao: Sun Yat-sen University
Rui-Hua Xu: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59193-4

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