Synthesizing multi-omics evidence of interface-specific selection in lung adenocarcinoma metastasis: A trait-origin-interface-function framework across lymph-node and brain ecosystems

Lung adenocarcinoma (LUAD) mortality is driven largely by metastatic progression, yet lymph-node metastasis (LNM) and parenchymal brain metastasis (BrM) arise in fundamentally different immune and anatomical ecosystems. Here, we present an integrative review that conceptually synthesizes published genomic, single-cell, spatial-transcriptomic, proteomic and metabolomic findings. Our trait-origin-interface-function (TOIF) framework maps individual claims to trait origin, anatomical interface, metastatic stage and functional output, with separate annotations for evidence type and study context. In LNM, lymphatic access and nodal occupation are associated with remodeling of antigen presentation, progenitor T-cell maintenance, lymphoid organization, and immune-cell export; however, evidence for individual tumor-immune communication axes remains uneven. In BrM, neurovascular entry, perivascular survival, glial-myeloid signaling, metabolic adaptation, and restricted effector access represent separable bottlenecks. Cross-platform evidence indicates that shared genomic ancestry can coexist with site-enriched transcriptional, immune, and metabolic states, while temporal and lineage-resolved measurements help distinguish their possible pre-existence, selective expansion and acquisition after tissue exposure. We therefore propose a TOIF framework that links each candidate mechanism to the omics layers that support it, the spatial context in which it operates, and the experiment needed to test causality. This framework clarifies why similar low-cytotoxicity phenotypes may reflect distinct mechanisms in nodal and brain lesions, and provides a basis for multi-omics biomarker development and stage-matched therapeutic investigation in LUAD metastasis.