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We sought biomarkers and molecular mechanisms of NCRT resistance in LARC. We analyzed paired pre-NCRT and post-NCRT biopsies from 26 patients with intermediate-to-high-risk LARC using single-cell RNA sequencing and spatial transcriptomics. Suboptimal responders showed pre-NCRT activation of NF-\u03baB, Wnt, Notch, VEGF, fatty acid, and glutamate pathways, whereas optimal responders exhibited higher cell-cycle and oxidative phosphorylation activity in tumor cells. We experimentally validated that NF-\u03baB inhibition increased chemoradiation sensitivity in colorectal cancer cells. Matrix cancer-associated fibroblasts (mCAFs), characterized by transforming growth factor-\u03b2\/extracellular matrix programs, preferentially interacted with NF-\u03baB-high tumor cells and immunosuppressive populations in suboptimal responders, whereas optimal responders exhibited cytotoxic CD8\u207a T cell expansion and conventional dendritic cell-2 enrichment. Spatial mapping revealed mCAF-dense, extracellular matrix-rich niches colocalized with NF-\u03baB-rich tumor-adjacent regions in suboptimal cases. Synchronous rectal and sigmoid tumors from one patient shared suboptimal response with NF-\u03baB activation and mCAF enrichment, suggesting the resistance arises from adaptive epithelial-stromal programs rather than site-specific genetics. Collectively, integrated multicompartment signatures, rather than a single molecular profile, define an NCRT-resistant ecosystem in which tumor NF-\u03baB activation, mCAF enrichment, and immune suppression converge to sustain non-response. In line with this framework, combined NF-\u03baB and oxidative phosphorylation scores stratified response status with robust performance (area under the curve\u2009=\u20090.875) and highlighted resistance-associated therapeutic targets.<\/jats:p>","DOI":"10.1038\/s12276-026-01792-2","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:04:26Z","timestamp":1785830666000},"page":"2643-2653","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NF-\u03baB-active tumors with matrix CAFs and suppressive immunity as key resistance mechanisms to chemoradiation in rectal cancer"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0436-8614","authenticated-orcid":false,"given":"Junseong","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-4336","authenticated-orcid":false,"given":"Sun","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Woong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dokyeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumin","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Ho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhyeok","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sug Hyung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"1792_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. 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