Related Experiment Video
Updated: Sep 28, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy
Wenjun Xiong1,2, Xueliang Gao3, Tiantian Zhang2
1Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Abstract:
Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.
Insights
Inhibiting USP8 enhances anti-PD-1/PD-L1 immunotherapy by increasing PD-L1 and activating immune responses. This combination therapy shows promise for improving cancer treatment efficacy and patient survival.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Anti-PD-1/PD-L1 immunotherapy offers significant cancer treatment benefits.
- Understanding resistance mechanisms to PD-1/PD-L1 blockade is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of USP8 in regulating anti-PD-1/PD-L1 immunotherapy efficacy.
- To explore the molecular mechanisms by which USP8 inhibition impacts the tumor microenvironment and immune response.
Main Methods:
- Utilized USP8 inhibitors in combination with PD-1/PD-L1 blockade in murine tumor models.
- Investigated changes in PD-L1 protein levels, ubiquitination status, innate immune signaling, and T cell activation.
- Analyzed NF-κB signaling pathway activation and MHC-I expression.
Main Results:
- USP8 inhibition increased PD-L1 protein abundance via TRAF6-mediated K63-linked ubiquitination, preventing degradation.
- USP8 inhibition activated innate immune responses and MHC-I expression through NF-κB signaling.
- Combination therapy significantly enhanced CD8+ T cell activity, suppressed tumor growth, and improved survival in preclinical models.
Conclusions:
- USP8 inhibition is a viable strategy to enhance anti-PD-1/PD-L1 immunotherapy efficacy.
- Targeting USP8 reshapes the tumor microenvironment to be more inflamed and immune-permissive.
- This study presents a novel combined therapeutic approach for improved cancer treatment.
More Related Videos
Related Concept Videos
01:27Tumor Immunotherapy
02:17The Tumor Microenvironment