Macrophage metabolic rewiring underpins the distinct immunological architecture of invasive mucinous adenocarcinoma revealed through layered molecular profiling

Invasive mucinous adenocarcinoma (IMA) is a rare variant of lung adenocarcinoma whose biological underpinnings remain poorly resolved, and the factors governing its distinct clinical behavior are not fully understood. To elucidate the cellular architecture of IMA, we generated a high-resolution single-cell transcriptomic atlas from ten IMA tumors and performed comparative analyses against datasets from invasive non-mucinous adenocarcinoma (INMA). Our data revealed that the IMA tumor microenvironment is shaped by a pronounced reshaping of the myeloid compartment, characterized by the expansion of select macrophage populations displaying transcriptional signatures associated with regulatory and metabolically activated states. These macrophages constituted a dominant cellular component in IMA and were positioned at the center of immunomodulatory pathways within the tumor ecosystem. Concomitantly, IMA exhibited a sharp reduction of multiple T cell subsets, accompanied by transcriptional indicators of functional attenuation, and a shift in the B cell compartment toward quiescent phenotypes consistent with disrupted lymphoid organization. Together, these features point to a coordinated landscape of adaptive immune dysfunction. Cell-cell communication analyses further supported this immunological configuration, uncovering immunoregulatory signals specifically strengthened in IMA that involved macrophage-to-lymphocyte and macrophage-to-epithelial interactions absent in INMA. On the epithelial axis, IMA tumors displayed a prominent enrichment of a mucin-producing epithelial population with transcriptional programs associated with mucin secretion and structural remodeling. Pseudotemporal modeling identified a differentiation trajectory linking alveolar epithelial cells to mucin-producing cells, bifurcating between IMA and INMA and suggesting that IMA harbors a lineage evolution distinct from the non-mucinous counterpart. Taken together, these results define IMA as a tumor ecosystem in which a remodeled macrophage compartment intersects with epithelial specialization to reinforce an immunosuppressive microenvironment. By outlining the interplay between myeloid activation, adaptive immune impairment, and mucin-associated epithelial differentiation, this work provides a cellular framework for understanding the unique biology of IMA and highlights potential therapeutic avenues that may benefit its clinical management.