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<p>Immune checkpoint blockade (ICB) has shown substantial efficacy in microsatellite instability-high (MSI-H) colorectal cancer (CRC), but resistance to αPD-1 therapy remains a major clinical challenge. The role and mechanism of deubiquitinating enzymes in regulating αPD-1 resistance in CRC remain poorly understood. In this study, we used clinical cohorts and the MC38 mouse CRC model to investigate USP13 expression in αPD-1-sensitive and αPD-1-resistant tumors. The function of USP13 was evaluated using the MC38 syngeneic tumor model and flow cytometry, and the molecular mechanism underlying the interaction between USP13 and SOCS1 was explored by ubiquitination assays, co-immunoprecipitation, and adenovirus-mediated USP13 overexpression. We found that USP13 was significantly downregulated in αPD-1-resistant MSI-H CRC patients and in resistant MC38 tumors, and that USP13 expression was significantly associated with prognosis specifically in MSI-H CRC patients. Functionally, USP13 knockout promoted αPD-1 resistance in MC38 tumors and reduced CD8 + T-cell infiltration. Mechanistically, loss of USP13 enhanced JAK-STAT pathway activation, while USP13 interacted with SOCS1, increased SOCS1 protein stability, and mediated K63-linked deubiquitination of SOCS1. Collectively, these findings demonstrate that USP13 stabilizes SOCS1 by removing K63-linked ubiquitination, thereby restraining excessive JAK-STAT activation and reversing resistance to αPD-1 therapy in MSI-H CRC. Targeting the USP13-SOCS1 axis may therefore represent a promising combination immunotherapeutic strategy for MSI-H CRC.</p>

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USP13 stabilizes SOCS1 to reverse αPD-1 resistance in MSI-H colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年4月18日

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  • Zhijian Zheng,
  • Yuqi Ni,
  • Ming Wu,
  • Linchao Ding,
  • Hongyan Li,
  • Na Zhang,
  • Xiayun Jin,
  • Hongjuan Zheng,
  • Bingjing Jiang,
  • Sisi Wang,
  • Wenxia Xu,
  • Qinghua Wang,
  • Jianfei Fu

摘要

Immune checkpoint blockade (ICB) has shown substantial efficacy in microsatellite instability-high (MSI-H) colorectal cancer (CRC), but resistance to αPD-1 therapy remains a major clinical challenge. The role and mechanism of deubiquitinating enzymes in regulating αPD-1 resistance in CRC remain poorly understood. In this study, we used clinical cohorts and the MC38 mouse CRC model to investigate USP13 expression in αPD-1-sensitive and αPD-1-resistant tumors. The function of USP13 was evaluated using the MC38 syngeneic tumor model and flow cytometry, and the molecular mechanism underlying the interaction between USP13 and SOCS1 was explored by ubiquitination assays, co-immunoprecipitation, and adenovirus-mediated USP13 overexpression. We found that USP13 was significantly downregulated in αPD-1-resistant MSI-H CRC patients and in resistant MC38 tumors, and that USP13 expression was significantly associated with prognosis specifically in MSI-H CRC patients. Functionally, USP13 knockout promoted αPD-1 resistance in MC38 tumors and reduced CD8 + T-cell infiltration. Mechanistically, loss of USP13 enhanced JAK-STAT pathway activation, while USP13 interacted with SOCS1, increased SOCS1 protein stability, and mediated K63-linked deubiquitination of SOCS1. Collectively, these findings demonstrate that USP13 stabilizes SOCS1 by removing K63-linked ubiquitination, thereby restraining excessive JAK-STAT activation and reversing resistance to αPD-1 therapy in MSI-H CRC. Targeting the USP13-SOCS1 axis may therefore represent a promising combination immunotherapeutic strategy for MSI-H CRC.