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Targeting USP14 Enhances Immunotherapy Response by Reprogramming Tumor-Associated Macrophages in Colon Cancer

ABSTRACT: Combining immunotherapy with other treatments improves survival in colorectal cancer, yet some patients remain unresponsive. Tumor-associated macrophages (TAMs) are a key immune cell population driving this immunotherapy resistance and fostering an immunosuppressive microenvironment. To overcome this, we screened a deubiquitinating enzyme (DUB) library targeting TAMs and identified USP14 as specifically upregulated in TAMs. Inhibiting USP14 reversed their pro-tumor functions, promoted M1 polarization, enhanced tumor cell killing, and activated effector T cells. USP14 inhibition also increased PD-L1 expression on tumor cells, alleviating T-cell suppression. In vivo, combining a USP14 inhibitor with an anti-PD-1 antibody synergistically enhanced immunotherapy efficacy, suppressed tumor progression, and improved survival in a mouse colon cancer model. Thus, USP14 is a promising target to overcome immunotherapy resistance in colorectal cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE320101 | GEO | 2026/03/05

REPOSITORIES: GEO

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Project description:Cervical cancer is the most common cancer among women worldwide, predominantly caused by human papillomavirus (HPV) subtypes, particularly HPV 16 and 18. Although it is largely preventable through vaccination and early detection, cervical cancer remains a significant health issue, particularly in low- and middle-income countries, mainly due to acquired chemoresistance. This study explores the therapeutic potential of deubiquitinating enzymes (DUBs), with a focus on ubiquitin-specific proteases (USPs), in combating oncogenesis in cervical cancer. Using the TCGA database, we assessed the prognostic relevance of USP14, revealing that elevated levels of this enzyme correlate with poorer overall and disease-free survival among cervical cancer patients. In-silico analysis of publicly available gene expression datasets also indicates a significant upregulation of USP14 in cervical cancer tumor tissues compared to their paired normal tissues. USP14 expression was analyzed at both the RNA and protein levels across various cervical cancer cell lines, followed by assays for proliferation, metastasis, and invasion to assess the impact of USP14 depletion. Elevated USP14 expression was observed in the cervical cancer cell lines, and inhibiting USP14 resulted in significant reductions in cell proliferation, metastasis, and invasion. A novel USP14 inhibitor, IU-1, produced similar results. Proteomic analysis indicated that the lactate transporter MCT-4, a crucial metabolic regulator, was dysregulated following USP14 alteration. Immunoprecipitation studies confirmed stable interactions between USP14 and MCT-4. Cycloheximide and Deubiquitination assays further demonstrated that USP14 modulates MCT-4 stability via deubiquitination at specific sites. Additionally, docking studies and molecular dynamics simulations illustrated the interaction between USP14 and MCT-4. Furthermore, the lactate shuttle was evaluated following USP14 inhibition, demonstrating the effect of MCT-4 inhibition on lactate production in cervical cancer cells. Immunohistochemical analysis of retrospective tissue samples assessed the expression of USP14 and MCT-4 and their correlation with patient prognosis. Collectively, our findings highlight the vital role of USP14 in the oncogenic and metabolic processes of cervical cancer, suggesting their potential as therapeutic targets. This research enhances the understanding of the molecular mechanisms driving cervical cancer progression and underscores the need for targeted therapeutic strategies.

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Targeting USP14 Enhances Immunotherapy Response by Reprogramming Tumor-Associated Macrophages in Colon Cancer

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