2. Academic Validation
  3. Targeting USP14 enhances immunotherapy response by reprogramming tumor-associated macrophages in colon cancer

Targeting USP14 enhances immunotherapy response by reprogramming tumor-associated macrophages in colon cancer

  • iScience. 2026 Mar 13;29(5):115362. doi: 10.1016/j.isci.2026.115362.
Dan Xiao 1,  Jun Fang 2,  Hui Jian 2,  Yang Yu 2
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei Province 430000, China.
  • 2 Department of Gestrointestinal Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei Province 430000, China.
PMID: 42058892 DOI: 10.1016/j.isci.2026.115362
Abstract

Combining immunotherapy with Other treatments improves survival in colorectal Cancer (CRC), 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 CRC.

Keywords

Biochemistry; Cancer; Immunology.

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