Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8⁺ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

多发同步性肺癌（MSLC）构成肺癌的一种独特亚型。为了探索 MSLC 不同病理阶段的基因组和免疫异质性，我们使用单细胞 RNA 测序、单细胞 TCR 测序和批量全外显子组测序分析了来自 8 名患者的 16 个 MSLC。我们的研究表明，克隆独立的肿瘤具有由共享驱动突变驱动的趋同进化。然而，来自同一个体的肿瘤几乎没有表现出共同的突变，表明其起源独立。在从浸润前腺癌向浸润性腺癌的转变过程中，我们观察到 T 细胞表型的转变，其特征是 Treg 细胞增加和 CD8 ⁺ T 细胞耗尽，同时细胞毒性减弱。此外，侵袭性腺癌表现出更高的新抗原丰度和更多样化的 TCR 库，表明异质性更高。综上所述，尽管具有共同的遗传背景和环境暴露，我们的研究强调了 MSLC 在不同阶段的个体性，突出了它们独特的基因组和免疫特征。