Niche-resolved transcriptional programs and ΔNp63/NRF2-associated enrichment in post-chemoradiation esophageal squamous cell carcinoma

Abstract

Spatial organization in esophageal squamous cell carcinoma resection specimens after chemoradiation remains poorly characterized. We profiled 56 patients using Visium spatial transcriptomics and identified eight niches. All 37 evaluated transcriptional signatures showed marked variation across the five niches with adequate patient representation, revealing structured biological compartmentalization. ΔNp63/NRF2-associated enrichment was highest at the Tumor Leading Edge and lowest at the Stromal Boundary; within Fibro-Immune Niche spots, it was also higher in perineural-invasion-positive tumors. In exploratory analyses of patients with pathological regression Grades 1–2, higher inflammation-, ΔNp63/NRF2-, SPP1-, multigene radiotherapy-resistance-, and oncogenic-transcription-factor-associated enrichment in the Fibro-Immune Niche was associated with shorter failure-free survival. Related Fibro-Immune programs also showed concordant adverse trends in the full cohort, although independent prognostic value was not established in either analysis. Post-treatment Fibro-Immune programs provide biologically coherent candidates for independent validation.