{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:16:44Z","timestamp":1783577804173,"version":"3.55.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Lung adenocarcinoma (LUAD) progression from adenocarcinoma\n                      <jats:italic>in situ<\/jats:italic>\n                      (AIS) to minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) is accompanied by molecular heterogeneity and tumor microenvironment remodeling. Chaperone-mediated autophagy (CMA) regulates tumor cell homeostasis, metabolic adaptation, and stress responses, but its dynamic alterations and prognostic significance during the AIS\/MIA-to-IAC progression of LUAD remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated the single-cell transcriptomic dataset GSE189357 and the spatial transcriptomic dataset GSE189487 with bulk transcriptomic data from TCGA-LUAD, GTEx, and the GEO validation cohorts GSE31210 and GSE50081 to characterize CMA-related features during the AIS\/MIA-to-IAC progression of LUAD. CMA activity and myeloid remodeling were analyzed at the single-cell and spatial levels. Candidate genes were identified by combining tumor-normal differential expression analysis in TCGA-LUAD with weighted gene co-expression network analysis. Multiple machine learning algorithms were compared to construct and externally validate a prognostic model. Biological and clinical relevance was further assessed through clinicopathological, pathway, immune, cell-cell communication, drug sensitivity, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CMA-related activity showed marked cell-type specificity and spatial heterogeneity during the AIS\/MIA-to-IAC progression of LUAD, with the most prominent changes in the myeloid compartment. Myeloid re-clustering revealed enrichment of cDC2 and APOE+ lipid-associated TAMs in IAC, whereas FABP4+ metabolic TAMs and immature neutrophils decreased. By integrating tumor-normal differential expression analysis with weighted gene co-expression network analysis, 122 candidate genes were identified, and a 15-gene CMA-related prognostic signature was established using a random survival forest model. This signature showed robust prognostic stratification in TCGA-LUAD, GSE31210, and GSE50081. The high-risk group had poorer survival, more advanced stage, and enrichment of malignant pathways including GLYCOLYSIS, G2M CHECKPOINT, MTORC1 SIGNALING, E2F TARGETS, and MYC TARGETS. The low-risk group showed higher stromal and immune scores and stronger immune activity. THBS1 signaling was restricted to high-risk epithelial communication, with fibroblasts as the major signal senders.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments showed that MGP overexpression inhibited lung cancer cell proliferation, colony formation, migration, and invasion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study characterized CMA-related heterogeneity during LUAD progression from AIS to IAC and established a robust 15-gene prognostic signature. Fibroblast-derived THBS1 signaling and MGP may contribute to the high-risk phenotype and provide insight into early LUAD evolution and risk stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1875096","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:35:35Z","timestamp":1783575335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding early lung adenocarcinoma progression by single-cell and spatial transcriptomics reveals a CMA-related prognostic signature"],"prefix":"10.3389","volume":"17","author":[{"given":"Junkang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, The First Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pain and Rehabilitation, Liaoning Cancer Hospital & Institute","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8021","DOI":"10.3390\/jcm14228021","article-title":"Redefining the diagnostic and therapeutic landscape of non-small cell lung cancer in the era of precision 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