A MYC-LDHA-MCT4 expression program marks an SPP1/TREM2-centered macrophage state in pancreatic ductal adenocarcinoma

Introduction Pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune-checkpoint blockade, and the metabolic organization of its myeloid barrier is incompletely understood. Methods 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 in vitro siRNA perturbation of MYC, LDHA and SLC16A3 with conditioned-medium assays on THP-1-derived macrophage-like cells and primary human CD8+ T cells. Results 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. Discussion 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.