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

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.