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

GSE320101 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2026/03/05 Platform GPL24247
Summary
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.
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Direct links to NCBI, no account and no request form: the whole study as GSE320101_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 6 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1426383 and SRA study SRP678424. Searching any of these in the dataset finder brings you back here.

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