The "Young-Old" group may have a unique pulmonary immune microenvironment, resulting in a different ratio of incidence rates between the upper and lower lobes of the lungs compared to other age

Background Non-small cell lung cancer (NSCLC) shows substantial heterogeneity across age groups and tumor locations. However, the relationship between age, lobar distribution, and the pulmonary immune microenvironment remains insufficiently understood. This study aimed to identify age-specific patterns of NSCLC occurrence and explore potential immune mechanisms underlying these differences. Methods We retrospectively analyzed 121,436 surgically treated NSCLC cases from Shanghai Pulmonary Hospital between 2015 and 2024. Tumor location and age at onset were assessed across World Health Organization age categories. To investigate potential mechanisms, we analyzed 15 tumor-adjacent single-cell RNA sequencing samples from the E-MTAB-13526 dataset and validated cell-type composition changes using TCGA bulk RNA-seq deconvolution. Cell–cell communication, pseudotime trajectory, transcription factor activity, and functional enrichment analyses were performed to characterize immune alterations. Results The upper-to-lower lobe incidence disparity of NSCLC followed a curved age-related pattern and was most pronounced in the young-old (YO, 60–74 years) group, reaching an approximate ratio of 7:3. Single-cell analysis revealed that the YO group had distinct immune microenvironment features, especially abnormal proportions of myeloid cells and T cells. Among myeloid subsets, alveolar macrophages were markedly increased in the YO group and showed enrichment of metabolic remodeling, oxidative stress, senescence-related signatures, and M2-like polarization. STAT1 and STAT3 activity was elevated, suggesting involvement of the JAK/STAT pathway. In parallel, T-cell composition shifted toward higher CD4 + T-cell proportions and relatively lower CD8 + T-cell proportions in the YO group. Cell–cell communication analysis indicated prominent myeloid–T cell interactions, with MHC-II, prostaglandin, and galectin signaling among the key pathways. Conclusions The YO group exhibits a unique pulmonary immune microenvironment that may contribute to its distinct upper-versus-lower lobe NSCLC distribution. Altered alveolar macrophage abundance and T-cell polarization, potentially mediated through JAK/STAT-related immune remodeling, may represent important mechanisms linking age and tumor location in NSCLC.