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The tumor grows by avoiding the immune system and adapting to stress in the endoplasmic reticulum. The IRE1\u03b1\u2013XBP1 pathway is a key pathway for cells to sense stress in the endoplasmic reticulum and has a large effect on the immune system.\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    encodes a regulatory subunit of glucosidase II that helps keep the endoplasmic reticulum in balance by modifying how IRE1\u03b1 works. However, it is unclear how it affects tumor immunity. This study used clinical sample analysis, bioinformatic analysis, CRISPR\/Cas9-mediated gene deletion, cytokine profiling, macrophage co-culture, and zebrafish xenograft experiments to investigate the immunological role of\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    .\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    deficiency reduced basal IRE1\u03b1 phosphorylation but led to exaggerated activation under ER stress, including increased XBP1s and p-JNK signaling. IL-6 and IL-8 secretion was suppressed in\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    -knockout (KO) cancer cells, disrupting cytokine-mediated immune suppression. Conditioned media from\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    -KO cells enhanced M1 macrophage polarization in vitro, as evidenced by increased CD86\u207a macrophages and expression of key M1-polarization markers. These effects were corroborated in zebrafish xenografts, where\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    deficiency diverted the immune environment toward an M1-dominant phenotype. Analysis of clinical pleural effusion samples further validated these findings, revealing a significantly reduced M1\/M2 macrophage ratio in malignant versus benign conditions. Furthermore,\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    -KO cells exhibited increased susceptibility to ER stress-induced apoptosis and ferroptosis, along with impaired autophagy. In conclusion, our findings place\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    as a key regulator linking ER stress signaling with tumor immune evasion and cell death pathways. Targeting\n                    <jats:italic>PRKCSH<\/jats:italic>\n                    may represent a promising therapeutic strategy to promote ferroptosis and anti-tumor immunity in lung adenocarcinoma.\n                  <\/jats:p>","DOI":"10.1186\/s12935-025-04104-2","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T12:45:40Z","timestamp":1764938740000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PRKCSH deficiency promotes an anti-tumor immune microenvironment via UPR activation and M1 macrophage polarization"],"prefix":"10.1186","volume":"26","author":[{"given":"Guo","family":"Xiyuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Worapong","family":"Khaodee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Jianghua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyawan","family":"Bunpo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yulin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5829-1328","authenticated-orcid":false,"given":"Yuan","family":"Qing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4346-4422","authenticated-orcid":false,"given":"Ratchada","family":"Cressey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"issue":"21","key":"4104_CR1","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.2174\/0929867325666180117110259","volume":"25","author":"OI Chen","year":"2018","unstructured":"Chen OI, et al. 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