Tuning Immune-Cold Tumor by Suppressing USP10/B7-H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Tuning the tumor microenvironment from "immune-cold" to "immune-hot" is crucial for enhancing cancer treatments, including immunotherapies and antibody-drug conjugates (ADCs).
• The B7-H4 protein is an immunosuppressive molecule implicated in cancer progression and treatment resistance.

Purpose of the Study:

• To investigate the role of the USP10/B7-H4 axis in regulating tumor immune responses and the efficacy of antibody-drug conjugates (ADCs).
• To explore the potential of targeting this axis as a therapeutic strategy for triple-negative breast cancers (TNBCs).

Main Methods:

• Multiomic analyses were employed to identify key molecular players.
• Experimental validation was conducted in preclinical TNBC models.
• The study focused on the deubiquitinase USP10 and its effect on B7-H4 stability and function.

Main Results:

• The deubiquitinase USP10 stabilizes B7-H4 by inhibiting its ubiquitylation, leading to suppressed tumor immunity and reduced efficacy of sacituzumab govitecan (SG).
• Pharmacological inhibition of USP10 promotes B7-H4 degradation, enhancing tumor immunogenicity and improving SG's tumor-killing effect.
• Suppression of the USP10/B7-H4 axis demonstrated efficacy in preclinical TNBC models, particularly those with high USP10 and B7-H4 expression.

Conclusions:

• The USP10/B7-H4 proteolytic axis is a critical regulator of tumor immune evasion and ADC treatment response.
• Targeting USP10 to induce B7-H4 degradation represents a novel therapeutic strategy to enhance cancer immunotherapy and ADC efficacy.
• This approach holds promise for treating triple-negative breast cancers and potentially other malignancies characterized by B7-H4 overexpression.