Colorectal cancer creates a suppressive tumor immune microenvironment that leads to tumor progression and resistance to immune checkpoint inhibitor therapy. Ubiquitin-specific protease 15 (USP15) broadly regulates immune responses and immune cell differentiation, but its involvement in shaping the tumor immune microenvironment of colorectal cancer remains unclear. This study demonstrated that USP15 is overexpressed in colorectal cancer and correlated with a poor prognosis. Employing colon orthotopic and metastatic tumor models, we performed loss- and gain-of-function assays for USP15 and revealed that overexpression of USP15 promotes tumor progression by increasing the abundance of myeloid-derived suppressor cells (MDSC) and decreasing the presence of CD8+ T cells in the tumor microenvironment. Through in vitro co-culture models and rescue experiments, we observed that tumoral USP15 decreased T-cell abundance by promoting MDSC recruitment rather than directly affecting T cells. Mechanistically, we found that USP15 deubiquitinated SMYD3, thereby activating H3K4me3-mediated transcription and the release of CCL2, which subsequently recruited MDSCs. Treatment with a USP15 inhibitor improved the efficacy of PD-1 blockade in colorectal cancer models. In a cohort of patients with colorectal cancer undergoing immunotherapy, we observed that those with high USP15 expression had a poor response to anti-PD-1 therapy. In summary, this research explored how USP15 facilitates the recruitment of MDSCs and identified it as a promising target for enhancing immunotherapy in colorectal cancer.
©2025 The Authors; Published by the American Association for Cancer Research.