Ubiquitylation-oxaliplatin-related prognosis signature reveals the landscapes of immune responses, cell communication, and therapeutic sensitivity for colorectal cancer.

Ubiquitylation plays a crucial role in posttranslational modification, and its dysregulation is linked to chemosensitivity. However, its role in oxaliplatin (OXA) resistance in colorectal cancer (CRC) remains unclear. Transcriptomic data from the cancer genome atlas (TCGA) and Gene Expression Omnibus were used to develop a ubiquitylation-OXA resistance-related risk score (URGScore), integrating immunological, mutational, and clinical features. Single-cell RNA sequencing (scRNA-seq) identified OXA-resistant cell populations, and Genomics of Drug Sensitivity in Cancer predicted drug sensitivity. GSVA analyzed enriched pathways. Ubiquitin-specific protease 7 (USP7) expression and function were validated in CRC. A 10-gene OXA resistance signature effectively classified CRC patients into OXA-sensitive or -resistant groups. Low-URGScore patients showed greater benefit from immunotherapy. scRNA-seq highlighted the MK signaling pathway, particularly in dendritic cells and progenitors, with NCL as a key MK receptor directly interacting with USP7. Potential drugs for high-risk patients were identified. Functionally, USP7 promoted CRC proliferation, invasion, and OXA resistance in vitro. We generated an ubiquitylation-OXA-resistant CRC risk model that was employed to provide potential therapeutic targets and strategies for treating CRC patients exhibiting OXA-resistance.