In epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC), clinical observations have consistently shown that female patients tend to achieve more favorable therapeutic responses and superior survival outcomes compared to male patients. However, the underlying biological mechanisms driving this gender-based discrepancy remain poorly understood. To investigate gender-associated intertumoral transcriptional variations, bulk RNA-sequencing (RNA-seq) datasets were analyzed. Additionally, immunohistochemistry (IHC) was employed to quantify programmed death-ligand 1 (PD-L1) expression in tumor cells. For a more refined characterization, digital spatial profiling (DSP) was performed on 21 EGFR -mutated lung adenocarcinoma (LUAD) tissue samples, aiming to dissect transcriptomic differences between male and female groups in three key compartments: tumor cells (TC), immune cells (IM), and macrophages (MA), respectively. Finally, IHC was performed to validate the findings. RNA-sequencing analysis identified gender-associated differences in gene expression, signaling pathways, and immune landscapes. Compared to male tumors, female tumors showed downregulation of KRAS signaling pathway and upregulation of DNA damage-related signature UV response. DSP uncovers transcriptomic differences in TC, IM, and MA compartments. TC segment from male patients exhibited significantly enriched signatures of cell proliferation, invasion, and metastasis, whereas IM segment showed increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and upregulated expression of the inhibitory immunomodulator CD276. These findings identify gender-associated molecular and immunological hallmarks of EGFR -mutated LUAD, emphasizing gender’s role in optimizing clinical management and informing gender-specific therapeutic development.
Yang et al. (2026) studied this question.