Single-cell transcriptomic analysis identifies a tumor-enriched GIMAP7⁺ CD4⁺ naïve T cell population with a unique immunoregulatory state in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is characterized by complex immune microenvironments that modulate disease progression and response to therapy. CD4⁺ naïve T cells are traditionally considered precursors of effector T cells, yet their functional states within LUAD remain poorly defined. We integrated single-cell RNA sequencing (scRNA-seq) data from LUAD tumor and distal normal tissues with bulk RNA-seq datasets (GSE159857 and TCGA-LUAD) to characterize CD4⁺ naïve T cell heterogeneity. Subclustering, trajectory analysis, cell-cell communication inference, and transcription factor network analysis were applied to identify tumor-associated states. qPCR was conducted to validate the differential expression of key transcription factors and hub genes in LUAD tissues. CD4⁺ naïve T cells were selectively expanded in LUAD and transcriptionally reprogrammed. A GIMAP7-high subpopulation was enriched in tumors, occupied early pseudotime states, and exhibited elevated LTB expression with distinct CCR6 dynamics. Functional enrichment analyses revealed upregulation of cytokine-mediated signaling and T cell receptor pathways, alongside downregulation of cytotoxic programs. Cell-cell communication analysis demonstrated enhanced interactions of GIMAP7⁺ cells via MHC-I, MHC-II, and Cyclophilin A (CypA) pathways. SCENIC analysis revealed downregulation of key transcription factors (EOMES, TBX21, SPI1), suggesting constrained effector differentiation. Bulk RNA-seq validation confirmed LTB upregulation and expansion of GIMAP7⁺ CD4⁺ naïve T cells. qPCR confirmed the decreased expression of TBX21 and SPI1, along with elevated levels of LTB and LTA in LUAD tissues. Our study identifies a tumor-enriched GIMAP7⁺ CD4⁺ naïve T cell population in LUAD that defines an immunoregulatory T cell state characterized by LTB-driven signaling, enhanced intercellular communication, and impaired effector differentiation. These findings provide new insights into tumor-immune interactions and highlight potential targets for immunomodulatory therapies.