Single-cell transcriptomic analysis reveals RNA-binding protein dysregulation in immune checkpoint inhibitor–induced colitis

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing antitumor immunity, but their use is frequently complicated by immune-related adverse events, particularly ICI-induced diarrhea and colitis. Growing evidence suggests that RNA-binding proteins (RBPs), which are critical post-transcriptional regulators of immune responses, may play a pivotal role in inflammatory diseases. To systematically investigate the involvement of RBPs in ICI-induced colitis, we performed a comprehensive reanalysis of published single-cell RNA sequencing data from CD45+ immune cells isolated from ICI colitis patients, ICI-treated noncolitis patients, and healthy control subjects. Our analysis revealed distinct, cell-type-specific RBP expression patterns across immune cell populations, with several RBP clusters (e.g. R4 in innate lymphoid cells and T cells, R5 in T cells, R8 in IgA+ plasma B cells, and R10 in B cells) being uniquely enriched in ICI colitis samples, suggesting their potential involvement in colitis pathogenesis. Further subpopulation analysis identified ICI colitis-deregulated RBPs: RPL26 was markedly downregulated in both innate lymphoid cells and T cells from ICI colitis patients, while PCBP2, ISG20, HSPA1A, and HSPA1B were upregulated in T cells. A colitis-specific RBP cluster was identified in B cells, among which ISG20 and ZFP36L2 showed elevated expression in specific subpopulations from colitis patients. ZFP36L2 potentially targets CD83 and JUNB, as their expression decreased in mouse germinal center B cells upon ZFP36L2 knockout. These findings highlight the regulatory role of RBPs in ICI-induced colitis and identify cell-type-specific alterations that may drive disease progression. Importantly, we pinpoint immune checkpoint-related RBPs as potential therapeutic targets, offering new strategies to manage this clinically significant immune-related adverse events.