{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:49:59Z","timestamp":1792601399552,"version":"4.5.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but frequently induce immune-related adverse events (irAEs), which can disrupt treatment and worsen outcomes. The mechanisms predisposing certain individuals to irAEs remain unclear, and reliable strategies for early prediction and prevention are urgently needed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed pre-treatment peripheral blood mononuclear cell (PBMC) transcriptomic data from 88 patients receiving ICIs, including 22 who subsequently developed irAEs. Immune infiltration signatures were used to build machine learning models with SHAP-based interpretability. Immune-related differentially expressed genes were then incorporated into the Chemical-Induced Gene Signature (CIGS) framework to predict candidate reversal compounds. Selected compounds were further evaluated in Jurkat T cells to experimentally validate their effects on interferon-\u03b3 signaling and underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Baseline immune infiltration patterns showed strong predictive value for subsequent irAE development, with the Random Forest model achieving the best performance (AUC = 0.97). SHAP analysis revealed that activated T-cell and NK-cell signatures were dominant predictors, indicating a pre-existing immune-primed state in irAE-prone individuals. Single-cell analysis identified two irAE-enriched myeloid clusters with lung-associated inflammatory features, suggesting baseline myeloid priming. T cells and NK cells from irAE samples exhibited marked upregulation of interferon-stimulated genes and strong enrichment of type I and type II interferon pathways. Perturbation-based screening identified multiple compounds capable of reversing these interferon-amplified signatures, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments demonstrated that alpinetin and momelotinib suppress interferon-\u03b3 signaling through distinct STAT1-and JAK\u2013STAT\u2013dependent mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>irAEs may arise from the convergence of pre-existing myeloid inflammation and interferon-driven lymphocyte activation before therapy. Our study provides a predictive framework for identifying high-risk patients and highlights mechanistically grounded compounds for potential irAE mitigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1798845","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:54:57Z","timestamp":1778219697000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Interferon-primed immune landscapes predict immune-related adverse events during immune checkpoint inhibitor therapy"],"prefix":"10.3389","volume":"14","author":[{"given":"Juanjuan","family":"Kang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Southwestern Chinese Medicine Resources, and Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, North Sichuan Medical College","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Chen","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Clinical School of Medicine, North Sichuan Medical College, Institute of Neurological Diseases","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Yong","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, China"]},{"name":"Sichuan Branch of National Clinical Research Center for Digestive Diseases","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyu","family":"Ao","sequence":"additional","affiliation":[{"name":"Chengdu Integrated TCM&Western Medicine Hospital","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Affiliated Hospital of North Sichuan Medical College","place":["Nanchong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"749064","DOI":"10.3389\/fonc.2021.749064","article-title":"Immune-related adverse events in PD-1 treated melanoma and impact upon anti-tumor efficacy: a real world analysis","volume":"11","author":"Bastacky","year":"2021","journal-title":"Front. 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