What question did this study set out to answer?

This research investigates the biological differences between multiple primary lung cancer (MPLC) and solitary primary lung cancer (SPLC), focusing on tumor characteristics and immune environment.

May 20, 2026

A80-2-09 Tumor Heterogeneity and Distinct Immune Microenvironment of Multiple Primary Lung Cancer

Q: What does this research mean for the field?

Multiple primary lung cancer (MPLC) is characterized by field cancerization-driven tumorigenesis, oxidative phosphorylation dependency, and a unique immunocompetent microenvironment compared to solitary primary lung cancer. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

Key Points

This research investigates the biological differences between multiple primary lung cancer (MPLC) and solitary primary lung cancer (SPLC), focusing on tumor characteristics and immune environment.
Performed single-cell RNA sequencing on 29 samples from 13 individuals with either MPLC or SPLC.
Conducted integrated analyses including copy number variation estimation, tumor and immune cell annotations, and cell-cell communication.
Analyzed immune responses, specifically the presence of cytotoxic T cells and immunosuppressive cells.
MPLC showed significant copy number variations in normal lung tissues (P<0.001), supporting the field cancerization hypothesis.
MPLC tumors had lower malignancy with increased oxidative phosphorylation (P<0.01) and specific gene expression patterns linked to better prognosis (P<0.05).
The immune microenvironment of MPLC was marked by reduced Tregs and enhanced cytotoxic GZMB+ CD8+ T cells, while SPLC demonstrated a glycolytic metabolism and fibroblast-dominated stroma.

Abstract

Abstract Background Multiple primary lung cancer (MPLC) exhibits distinct clinicopathological features and poor response to EGFR-TKIs, yet its underlying biology remains unclear. Methods We performed single-cell RNA sequencing (scRNA-seq) on 29 samples (14 tumors, 9 normal tissues) from 13 individuals (7 MPLC, 6 solitary primary lung cancer SPLC patients). Integrated analyses included copy number variation (CNV) inference, tumor cell annotation, immune cell annotation, and cell-cell communication mapping. Results MPLC demonstrated significant CNVs in histologically normal lung tissues (P0.001), supporting the field cancerization hypothesis. Tumor cells in MPLC exhibited lower malignancy, evidenced by enrichment of alveolar differentiation genes (*SFTPA1/SFTPA2*; favorable prognosis in TCGA-LUAD, P0.05); preferential oxidative phosphorylation (OXPHOS) over glycolysis (P0.01), linked to DNMT1high/NNMTlow expression; reduced immunosuppressive Tregs and expanded cytotoxic GZMB+ CD8+ T cells and CD16+ NK cells (P 0.001); MPLC-specific TNFA-NFKB pathway activation was observed in T cells and macrophages (CCL3+/AZU1+ subsets). In contrast, SPLC showed fibroblast-dominated stroma and glycolytic metabolism. Conclusion MPLC is characterized by field cancerization-driven tumorigenesis, OXPHOS dependency, and a unique immunocompetent microenvironment. Therefore, this study reveals the difference of tumorigenesis between MPLC and SPLC and provides a potential immunotherapy strategy for MPLC. This abstract is funded by: None

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A80-2-09 Tumor Heterogeneity and Distinct Immune Microenvironment of Multiple Primary Lung Cancer

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