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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune-checkpoint blockade, and the metabolic organization of its myeloid barrier is incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated imaging mass cytometry from the phase II trial NCT04177810, three single-cell RNA-seq datasets, two spatial transcriptomic cohorts (12 sections), three survival cohorts, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      siRNA perturbation of MYC, LDHA and SLC16A3 with conditioned-medium assays on THP-1-derived macrophage-like cells and primary human CD8+ T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CD8+ T-cell infiltration increased without objective responses while macrophages remained abundant. Patient-level epithelial MYC and glycolysis programs correlated with SLC16A3 (MCT4) and a macrophage lactate-reception program. Across 12 spatial sections, macrophage-receiver scores were higher around MCT4-high cores (ring 1: 12\/12 positive; median difference 0.433; FDR = 0.010), with the strongest state-resolved signal for SPP1\/TREM2 macrophages (median difference 0.613; FDR = 0.006); the composition-adjusted effect remained positive (10\/12) but was non-significant (FDR = 0.071). Silencing MYC, LDHA or SLC16A3 reduced extracellular lactate and altered conditioned-medium effects, with partial rescue by lactate add-back. Survival associations were cohort-dependent with substantial heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These results define an exploratory, expression-based spatial association between a tumor MYC-LDHA-MCT4 program and an SPP1\/TREM2-centered macrophage state, constituting a testable hypothesis rather than evidence of lactate transfer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1978427","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T05:31:25Z","timestamp":1791178285000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A MYC-LDHA-MCT4 expression program marks an SPP1\/TREM2-centered macrophage state in pancreatic ductal adenocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Qianqian","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hequn","family":"He","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital of Ningbo University","place":["Ningbo, Zhejiang, 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