{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:32:35Z","timestamp":1786627955632,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Colorectal cancer progression and therapeutic response are determined not only by tumor-intrinsic programs but also by neural, stromal, and immune components of the tumor microenvironment. However, biologically interpretable transcriptomic scores that jointly capture neural\/stromal remodeling and immune activation remain limited. We developed a neuro-immune score (NIS), defined as the neural\/stromal module score minus the immune activation module score. NIS was constructed using the combined TCGA-COAD\/READ colorectal cancer cohort and externally evaluated in independent Gene Expression Omnibus (GEO) datasets. Single-cell RNA sequencing, focused ligand\u2013receptor analysis, and spatial transcriptomics were further integrated to characterize the cellular origins, spatial organization, and potential mechanisms underlying NIS-associated biology. A high NIS (NIS-high) was associated with adverse prognosis in bulk transcriptomic cohorts. External validation demonstrated that a high NIS was significantly associated with worse disease-free survival\/relapse-free survival (DFS\/RFS) in GSE39582 and worse overall survival in GSE17536. A multi-cohort meta-analysis further supported a consistent association between NIS-high and poor clinical outcomes. Single-cell analysis localized the NIS-high signal mainly to glial-like cells, fibroblasts, pericytes, endothelial cells, and malignant epithelial cells, whereas CD8+ T cells and natural killer cells exhibited low NIS. Focused ligand\u2013receptor analysis suggested that NIS-high cellular compartments may communicate with immune and tumor compartments through MIF-CD74\/CXCR4, SPP1-CD44, extracellular matrix (ECM)\u2013integrin, TGF-\u03b2, and immune checkpoint-related axes. Spatial transcriptomics further demonstrated that NIS-high regions were enriched in stromal, neural\/glial-like, vascular\/pericyte, and tumor\u2013stromal niches, whereas NIS-low regions were associated with immune-activated and cytotoxic T\/NK cell-rich areas. NIS captures a spatially organized state of the colorectal cancer microenvironment characterized by neural\/stromal remodeling, activation of ECM and vascular\/pericyte niches, and relatively reduced or spatially segregated immune activation. NIS may serve as a biologically interpretable microenvironment stratification score associated with adverse outcomes. It also provides a framework for future studies targeting stromal remodeling, myeloid-mediated immune regulation, neural-associated signaling, and antitumor immunity.<\/jats:p>","DOI":"10.3390\/ijms27167231","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:47:11Z","timestamp":1786625231000},"page":"7231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A\u00a0Neuro-Immune Score Defines a Stromal\u2013Neural and Immune-Segregated Microenvironment Associated with Poor Prognosis in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Hui","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4329-4956","authenticated-orcid":false,"given":"Yanjun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.annonc.2024.02.008","article-title":"Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer","volume":"35","author":"Laskar","year":"2024","journal-title":"Ann. 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