Multifocal ground-glass opacities in lung cancer: a narrative review of genomic evolution, immune ecology, and biology-informed clinical management.

Background and Objective: Ground-glass opacity (GGO) is a computed tomography descriptor rather than a histologic diagnosis. Multifocal GGOs (mGGOs) are increasingly detected during lung cancer screening, yet their clonal origins, immune ecology, progression risk, and optimal management remain difficult to reconcile within conventional lung cancer frameworks. This narrative review evaluates genomic, immunologic, and clinical evidence relevant to mGGOs and examines how biological findings may inform surveillance and local treatment without encouraging overtreatment. Methods: PubMed/MEDLINE, Web of Science, Google Scholar, and selected guideline and trial sources were searched through 29 July 2026 for English-language studies published mainly from January 2020 to July 2026, supplemented by earlier landmark reports. Search concepts included mGGO, subsolid nodule, synchronous multiple primary lung cancer (SMPLC), clonality, single-cell and spatial transcriptomics (ST), immune microenvironment, active surveillance, and parenchyma-sparing surgery. Key Content and Findings: Many mGGO presentations are compatible with clonally independent synchronous primaries, although intrapulmonary metastasis (IPM) can occur and developmental mosaicism remains a single-study, selected-patient hypothesis. Early lesions may have low mutational burden and attenuated effector activity, but immunoediting, regulatory T-cell enrichment, dysfunctional CD8-positive T-cell states, and inhibitory non-classical antigen-presentation pathways can already be present in adenocarcinoma in situ or minimally invasive adenocarcinoma. We therefore use relative adaptive immune quiescence as a descriptive population-level term, not as evidence of absent immune pressure. Prospective ECTOP-1021 data support short-term feasibility of surveillance in a highly selected cohort, but do not establish comparative effectiveness. Conclusions: A biology-informed framework can refine risk discussion for selected patients with mGGOs, provided that radiologic terms are not treated as histologic diagnoses and mechanistic associations are not converted into clinical recommendations. Surveillance, local treatment, and parenchyma preservation should remain multidisciplinary and evidence-calibrated; biomarker-guided triage and interception strategies require prospective GGO-specific validation.