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Methylation-controlled J protein (MCJ; also known as DNAJC15) is a negative regulator of mitochondrial respiration, but its role in tumor metabolism remains unclear. To study the role of tumor-intrinsic MCJ expression, we generated MCJ-deficient cancer cell lines using siRNA and performed a comprehensive analysis of their characteristics in comparison with MCJ-expressing parental cells. MCJ deficiency resulted in enhanced mitochondrial respiration and ATP production. Despite normal growth in vitro, MCJ-deficient tumor cells exhibited severly curtailed growth in immunocompetent mice. However, these cells grew comparably to controls in T-cell-deficient athymic mice, indicating immune-mediated suppression. Tumors lacking MCJ exhibited increased immune cell infiltration and immunogenicity, as determined by immunohistochemistry and flow cytometry. Transcriptomic analysis revealed a metabolic shift from glycolysis-dominant and hypoxic conditions to a state favoring oxidative phosphorylation, which correlated with upregulation of immune-related pathways and enhanced anti-tumor immune responses. Bioinformatic analysis conducted to study the correlation between the level of MCJ expression and tumor functions in human colorectal cancer revealed that low MCJ expression correlated with increased tumor mutational burden, microsatellite instability, and immune cell infiltration, demonstrating the clinical relevance of MCJ expression in the context of colon adenocarcinoma. These findings suggest MCJ as a promising target for metabolic immunotherapy in cancer.<\/jats:p>","DOI":"10.1186\/s43556-026-00466-9","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T09:03:37Z","timestamp":1778490217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modulation of the immunogenic landscape in colorectal cancer by mitochondrial methylation-controlled J protein"],"prefix":"10.1186","volume":"7","author":[{"given":"Maram","family":"Ahmed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoja M.","family":"Haneefa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aftab","family":"Alam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh K.","family":"Kali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashraf","family":"Al-Sbiei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghada","family":"Bashir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alia","family":"Al-Bawardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ienas","family":"Idriss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yassir A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Batoul","family":"Khlaifat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heba T.","family":"Naser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Labania","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rifat","family":"Hamoudi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uday","family":"Kishore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir","family":"Attoub","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Rincon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalil B.","family":"Ramadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria J.","family":"Fernandez-Cabezudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-1938","authenticated-orcid":false,"given":"Basel K.","family":"Al-Ramadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"issue":"16","key":"466_CR1","doi-asserted-by":"publisher","first-page":"R921","DOI":"10.1016\/j.cub.2020.06.081","volume":"30","author":"NM Anderson","year":"2020","unstructured":"Anderson NM, Simon MC. 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