RBM15-mediated Metabolic Reprogramming Boosts Immune Response in Colorectal Cancer

Immune checkpoint blockade (ICB) offers therapeutic options for patients with advanced colorectal cancer; however, only a subset of patients with microsatellite instability-high (MSI-H) tumors respond to treatment. Therefore, strategies to enhance immunotherapy sensitivity are urgently needed. In this study, we demonstrate that RBM15 is highly expressed in colorectal cancer and is associated with poor prognosis. Loss of RBM15 increases the expression of fumarate hydratase (FH), leading to a reduction in its substrate fumarate, which acts as a suppressor of anti-tumor immunity. Notably, RBM15 depletion delays tumor growth by promoting CD8+ T cell infiltration. Our findings identify RBM15 as a key suppressor of anti-tumor immunity, suggesting that targeting RBM15 could be a promising therapeutic strategy in colorectal cancer. Overall design: To reveal the tumor-intrinsic functional role of RBM15 in colorectal cancer, we utilized the CRISPR/Cas9 gene editing system to knock out (KO) RBM15 in the human colorectal cancer cell line HCT15. We then performed differential gene expression analysis using data obtained from RNA-seq of WT or RBM15 knockout cells.