A Reproducible CD36-Enriched Lipid-Associated Macrophage State in Lung Adenocarcinoma and Its Spatial Relationship to Exhausted CD8+ T Cells

Background/Objectives: The reproducibility of lipid-associated macrophage (LAM) states in lung adenocarcinoma (LUAD) and their spatial relationship to exhausted CD8+ T cells are unclear. Methods: Single-cell RNA-sequencing cohorts (discovery, GSE131907; replication, GSE189357) were analyzed at patient level with selection-independent replication criteria. Spatial analyses used one Xenium section and one independent Visium HD specimen. Transcription-factor inference, CellChat and drug-target Mendelian randomization (MR) generated hypotheses. Results: A macrophage state combining lipid-handling/lysosomal (APOE, TREM2) and resident-like (FOLR2, SELENOP) features was recovered in both cohorts and every patient (held-out signature area under the curve, 0.91). CD36 enrichment was weaker in the replication cohort, hence the name CD36-enriched LAM. Inferred NR1H3/liver X receptor α (LXRα) activity was higher, but its magnitude depended on population-defining genes. Exhausted CD8+ T cells were modestly over-represented near CD36-enriched LAM in both specimens; adjustment for transcript depth and tissue region attenuated this excess. Predicted Galectin-9 and macrophage migration inhibitory factor (MIF) signals were not population-specific. MR found no evidence that genetically predicted CD36 expression affects LUAD risk (odds ratio 0.98; 95% confidence interval 0.95–1.01). Conclusions: CD36-enriched LAM is a reproducible LUAD macrophage state modestly associated in space with exhausted CD8+ T cells. The roles of CD36, LXRα, Galectin-9 and MIF require protein-level and functional testing.