A reproducible pretreatment mucosal-inflammatory-remodeling state is associated with induction-phase anti-tumor...

Primary non-response to anti-tumor necrosis factor (anti-TNF) therapy remains a major clinical challenge in ulcerative colitis (UC); however, public-data transcriptomic studies often yield unstable single-gene biomarkers and limited replication.

We analyzed three independent pretreatment UC mucosal transcriptome cohorts from infliximab-treated patients (total n = 79). The induction response was assessed at 4-8 weeks according to the original definition in each study. To prioritize cross-cohort biology over single-probe overlap, we integrated recurrent effect direction, pathway convergence, and sample-level scoring. We defined a 68-gene consensus signature for interpretation, evaluated generalization with leave-one-dataset-out (LODO) scoring, tested attenuation after adjusting for baseline inflammatory/remodeling proxies, and examined cellular localizations in public epithelial (GSE116222) and rectal immune (GSE125527) single-cell references.

The 68-gene consensus signature was higher in non-responders across all three cohorts. In the LODO analysis, the held-out non-response axis remained elevated in the held-out non-responders, with a pooled random-effects size of Hedges' g = 1.36 (95% confidence interval: 0.83-1.89; p = 5.65 × 10^-7; I² = 0%). The pathway analyses consistently implicated inflammatory responses, TNF-α/NF-κB, IL-6-JAK-STAT3, interferon signaling, hypoxia, and epithelial-mesenchymal transition (EMT), whereas oxidative phosphorylation was enriched in the responders. Adjustments for inflammatory proxies with and without EMT attenuated the effects, but the associations remained directionally positive in all cohorts and retained nominal significance in two cohorts under the strictest model. In public single-cell references, the signature activities were enriched in cycling/stem-like and stress-inflammatory epithelial states and were highest in the rectal myeloid/dendritic cells (M/DCs).

In the infliximab-treated UC cohorts, induction-phase non-response is associated with reproducible pretreatment mucosal-inflammatory-remodeling states that remain evident in the held-out cross-cohort analyses while localizing most strongly to rectal M/DCs and stress-associated epithelial states in public single-cell references. The signal overlaps substantially with the baseline inflammatory/remodeling burden, but its direction is consistent across the cohorts. These findings support a biologically coherent disease-state framework rather than a deployable clinical predictor.