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Abstract Esophageal squamous cell carcinoma (ESCC) stands as one of the most formidable and lethal cancers, necessitating urgent intervention. Despite extensive research efforts to identify optimal radiotherapy and chemotherapy strategies, complete response rates remain disappointingly low, and the challenge of swift relapse persists. Previous investigations primarily focused on primary tumors, utilizing single-omics approaches to illuminate cellular responses to chemotherapy and immunotherapy. However, our understanding of the mechanistic basis for chemoradiotherapy resistance in ESCC remains severely limited. In this study, we conducted multi-omics profiling of over 100 pre-treatment primary and post-treatment relapse ESCC tumors subjected to chemoradiotherapy from a clinical trial (ESO-Shanghai6; NCT04694391). Our comprehensive approach included whole-exome/genome sequencing (WES/WGS), bulk RNA-sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptome analyses. WES/WGS revealed that tumors with rapid relapse displayed high clonal diversity. Notably, 40% of ESCC relapse patients exhibited NFE2L2/KEAP1 somatic alterations in their primary tumors, correlating with a dismal prognosis. Consistent with these findings, downstream NRF2 signaling targets were upregulated in relapse tumors and radiotherapy-resistant cell lines. Further analysis of scRNA-seq and spatial transcriptome data provided profound insights into the spatial organization of mutation-driven, relapse-associated cell populations and their interactions within the tumor microenvironment (TME). Intriguingly, a subset of epithelial tumor cells characterized by NRF2 pathway activation was highly enriched in relapse tumors. Among immune cells, the infiltration proportions of SPP1+ macrophages and SPP1+TREM2+ macrophages—exhibiting higher myeloid immunosuppressive scores—tended to increase in relapse patients. Crucially, NRF2-signaling activated epithelial cells physically co-localized with SPP1+TREM2+ macrophages exclusively in relapse samples, while SPP1+ macrophages were present in both primary and relapse samples. Interaction analysis suggested that NRF2-signaling activated epithelial cells recruit SPP1+TREM2+ and SPP1+ macrophages, thereby fostering an immunosuppressive TME and promoting post-radiotherapy relapse. In summary, our study provides a comprehensive understanding of the molecular determinants influencing ESCC tumor responses under chemoradiotherapy. NFE2L2/KEAP1 mutations emerge as predictive markers for stratifying ESCC patients, and targeting NRF2 signaling presents a potential avenue to overcome resistance to chemoradiotherapy in this challenging disease. Citation Format: Kuaile Zhao, Hu Chen, Zhenzhen Xun, Jiaying Deng, Yikai Luo, Jinjun Ye, Junqiang Chen, Weiwei Chen, Jun Li, Han Liang. Comprehensive multi-omics analysis unveils NFE2L2/KEAP1 mutations as key drivers of treatment resistance in esophageal squamous cell carcinoma during chemoradiotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB003.
Zhao et al. (Fri,) studied this question.