Single-cell profiling reveals FAM117A as a key regulator linking macrophage–epithelial crosstalk with the progression of lung adenocarcinoma

The tumor microenvironment (TME) has a profound influence on the progression of lung adenocarcinoma (LUAD) and its response to therapy. We identified a tumor-promoting communication network based on single-cell RNA sequencing. This shows an SPP1 + macrophage and basal epithelial cell communication module (CIM) that is enriched in invasive portions of tumors, and spatially associated with decreased cytotoxic T cell activity and poor prognosis. Transcriptomic modeling identified FAM117A as a major suppressor of the CIM network. FAM117A is a DYRK1A-interacting cell-cycle regulator. Loss of FAM117A resulted in longer G1/S transition time, increased cell proliferation, and an enhanced macrophage-epithelial feedback loop. Immunohistochemical studies showed decreased FAM117A expression in LUAD tissues, which correlated with SPP1 + macrophage density and poor outcome. Treatment with FAM117A or pharmacological inhibition of CDK4/6 reduced the in vitro and in vivo tumor growth. Thus, FAM117A links intrinsic cell cycle regulation with the extrinsic immune microenvironment, providing a rationale for combined therapies that address macrophage-tumor and cell cycle regulatory events in LUAD.