AimTo decipher the difference in TME between younger and elder patients with lung cancers.FindingsEpithelial cells were the predominant component of the TME in younger patients, whereas T/NK cells were the predominant cell type in the TME of elderly patients.Compared to younger patients, the pathway of natural killer cell-mediated cytotoxicity was down-regulated in NK cells derived from elder patients; Moreover, CXCL13 was significantly upregulated in T/NK cells from elder patients and was mainly expressed by exhausted CD8+T cells in elder patients.TANs were identified in elderly patients, while ISG15+ macrophages were identified in younger patients.Different cell-to-cell communication patterns in younger and elder patients.MessageDistinct immune profiles between younger and elderly patients. PurposeThe immune profiles of elder patients with non-small cell lung cancer (NSCLC) differ significantly from those of younger patients. The tumor microenvironment (TME) is a crucial factor in cancer progression and therapeutic responses. The present study aims to decipher the difference in TME between younger and elderly patients with lung cancers.MethodsWe downloaded single-cell RNA data from public databases. The algorithm of uniform manifold approximation and projection (UMAP) was applied to cluster and visualize single-cell sequencing data. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) analysis were performed to evaluate the physiological functional characteristics in sub-group cells. CellPhoneDB was used to identify cell-cell interactions between immune cells within TME.ResultsWe conducted single-cell RNA sequencing on 96,491 cells from elderly patients and 169,207 cells from younger patients, respectively. We observed that epithelial cells were the predominant component of the TME in younger patients, whereas T/NK cells were the predominant cell type in the TME of elderly patients. We also found that there was a higher proportion of Tregs and a lower proportion of NK, effector CD8+T and gamma delta T cells in elder patients compared with younger patients. In addition, a comparative GSEA analysis of NK cells between older and younger patients revealed that the pathways of Parkinson's disease, Alzheimer's disease, mismatch repair, and base excision repair were up-regulated in NK cells from elderly patients, while the pathways related to natural killer cell-mediated cytotoxicity and allograft rejection were downregulated. Furthermore, we identified tumor-associated neutrophils (TANs) in elder patients, and GSVA analysis demonstrated that the pathway of angiogenesis was upregulated, and the pathway of interferon_gamma_response, inflammatory_response, TNF alpha_signaling_via_NF kappa B pathways were downregulated. Importantly, the pro-inflammatory response scores of complement C1q C chain positive (C1QC+) macrophages, tissue-resident macrophages (TRM), non-classical monocytes (NCM), secreted phosphoprotein 1 positive (SPP1+) macrophages, and classical monocytes (CM) in elder patients were significantly lower compared to those in younger patients. Finally, cell-to-cell communication analyses unveiled the disparities in regulatory patterns between elder and younger patients, namely the pairs of CXCL13-ACKR4 and CSF1-SIRPA in elder patients and the pairs of CTLA4-CD86 and TIGIT-NECTIN2 in younger patients.ConclusionThis study reveals the distinct immune profiles between younger and elder NSCLC patients, and the elder patients were likely to exhibit a more immunosuppressive TME and attenuated tumor-killing capability compared with younger patients.