Single-cell analysis reveals immunotherapy-induced epithelial state remodeling and identifies PLAUR as a prognostic biomarker in colorectal cancer

Immune checkpoint blockade has achieved durable responses in a subset of colorectal cancer (CRC) patients; however, the majority derive limited benefit. While previous studies have largely focused on immune cell dynamics, how tumor epithelial cells adapt to immune selection pressure during immunotherapy remains insufficiently characterized. Here, we analyzed single-cell RNA sequencing data from colorectal tumor samples collected before and after immunotherapy, including anti-PD-1 monotherapy and anti-PD-1 combined with celecoxib, to systematically dissect treatment-associated epithelial cell remodeling. We identified five distinct epithelial subpopulations exhibiting marked changes in composition, developmental trajectories, and cell–cell communication following therapy. Pretreatment epithelial cells displayed strong extracellular matrix-related and inflammatory signaling, consistent with invasive and immune-evasive phenotypes. Immunotherapy induced a bifurcation of epithelial cell fate toward either a normal-like, differentiated state with restored metabolic homeostasis and genomic stability, or a PD-1-associated, repair-like state characterized by active cell-cycle and stress-response programs. Integrative prognostic modeling across retrospective CRC cohorts identified PLAUR as a candidate risk-associated gene. Higher PLAUR expression was associated with poorer survival and transcriptional features related to epithelial–mesenchymal transition and immune dysfunction. In addition, TIDE-based computational analysis predicted a lower likelihood of immunotherapy response in patients with higher PLAUR expression; however, this association was not directly validated in an independent immunotherapy-treated cohort. Together, our findings provide a single-cell-level framework for understanding treatment-associated epithelial plasticity in CRC and nominate PLAUR as a computationally derived candidate marker that warrants further experimental and prospective clinical validation.