{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:27:59Z","timestamp":1785421679046,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 2019 \u2013 ID 23,381"],"award-info":[{"award-number":["IG 2019 \u2013 ID 23,381"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IG 2019 \u2013 ID 23,381"],"award-info":[{"award-number":["IG 2019 \u2013 ID 23,381"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Italian Ministry of Health\u2014Ricerca Corrente Annual Program 2027"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Mucinous adenocarcinoma (MAC) is a rare and clinically problematic subtype of rectal cancer, tending to present at an advanced stage and to respond poorly to neoadjuvant therapy. The consistently worse prognosis than that of not-otherwise-specified adenocarcinoma (NOS-AC) is not fully understood, potentially owing to intrinsically more aggressive biology or specific immune evasion mechanisms. We used the IMMUNOREACT multicentre cohort, with external validation in TCGA, to investigate the clinical and immunological features of rectal MAC in detail. Methods: Two hundred patients with rectal adenocarcinoma (16 MAC, 184 NOS-AC) from the IMMUNOREACT 1 (NCT04915326) and IMMUNOREACT 2 (NCT04917263) prospective cohorts were included. To account for the imbalance in baseline characteristics, propensity score matching (PSM) was performed on age, sex, neoadjuvant treatment and TNM stage. The immune microenvironment was characterised using immunohistochemistry (CD3, CD4, CD8, CD8\u03b2, Tbet, FoxP3, PD-L1, MSH6, PMS2, CD80), flow cytometry and NanoString PanCancer IO 360\u2122 transcriptomics of adjacent healthy mucosa. Findings were externally validated against TCGA rectal and colon adenocarcinoma datasets. Results: MAC presented at significantly more advanced stage than NOS-AC across all TNM parameters: higher T stage (p = 0.006), N stage (p &lt; 0.001), M stage (p = 0.039) and overall TNM stage (p &lt; 0.001). In the unmatched cohort, MAC was associated with worse overall survival (HR 2.53; 95% CI 1.03\u20136.23; p = 0.043) and disease-free survival (HR 2.86; 95% CI 1.25\u20136.55; p = 0.013), but both differences became non-significant after PSM. MAC patients had higher haemoglobin after adjusting for confounders (mean difference [MD] 1.26 g\/dL, 95% CI 0.30\u20132.31, p = 0.012), consistent with a hypothesis of reduced chronic rectal bleeding as a possible mechanism for late presentation. Transcriptomically, MAC showed suppression of HLA class II antigen presentation genes (HLA-DQA1, HLA-DQB1, HLA-DRB1) and myeloid activation genes (S100A8\/A9\/A12) in adjacent healthy mucosa. Loss of MMR proteins MSH6 and PMS2 in histologically normal mucosa was significantly more frequent in MAC. These findings were replicated in the TCGA cohort, which also showed lower tumour mutational burden and a distinct mucin-associated transcriptomic profile in MAC. Conclusions: The worse outcomes of rectal MAC appear to be driven largely by late-stage presentation, possibly owing to later diagnosis. MAC nonetheless carries a distinct immune phenotype, detectable even in histologically normal surrounding mucosa, that likely contributes to its treatment resistance. These observations provide a basis for developing histotype-specific approaches to both early detection and treatment in this uncommon but clinically challenging tumour subtype.<\/jats:p>","DOI":"10.3390\/cancers18121943","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:57:58Z","timestamp":1781513878000},"page":"1943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ill Fate of Rectal Mucinous Adenocarcinoma: A Defect in Immunosurveillance or a Mucin Coating Effect?\u2014The IMMUNOREACT 20 Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Lorenzo","family":"Dell\u2019Atti","sequence":"first","affiliation":[{"name":"Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1591-1320","authenticated-orcid":false,"given":"Andromachi","family":"Kotsafti","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-2322","authenticated-orcid":false,"given":"Francesca","family":"Galuppini","sequence":"additional","affiliation":[{"name":"Department of Integrated Diagnostics, Azienda Ospedale-Universit\u00e0 Padova, 35128 Padova, Italy"},{"name":"Department of Medicine, University of Padova School of Medicine, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7055-635X","authenticated-orcid":false,"given":"Melania","family":"Scarpa","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3920-8348","authenticated-orcid":false,"given":"Roberta","family":"Salmaso","sequence":"additional","affiliation":[{"name":"Department of Integrated Diagnostics, Azienda Ospedale-Universit\u00e0 Padova, 35128 Padova, Italy"},{"name":"Department of Medicine, University of Padova School of Medicine, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0323-0955","authenticated-orcid":false,"given":"Astghik","family":"Stepanyan","sequence":"additional","affiliation":[{"name":"Chirurgia Generale 3, Azienda Ospedale Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Sbaraglia","sequence":"additional","affiliation":[{"name":"Department of Integrated Diagnostics, Azienda Ospedale-Universit\u00e0 Padova, 35128 Padova, Italy"},{"name":"Department of Medicine, University of Padova School of Medicine, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6489-8049","authenticated-orcid":false,"given":"Luca Maria","family":"Saadeh","sequence":"additional","affiliation":[{"name":"Chirurgia Generale 3, Azienda Ospedale Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Tussardi","sequence":"additional","affiliation":[{"name":"Chirurgia Generale 3, Azienda Ospedale Universit\u00e0 di Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rosato","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy"},{"name":"Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche (DISCOG), University of Padova, 35128 Padova, 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