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Abstract

Regulatory T cells (Treg) play immunosuppressive roles in lung cancer and are key biomarkers in cancer immunology. Using scRNA-seq and stereo-seq, we aimed to identify a novel circulating Treg subtype in non-small cell lung cancer (NSCLC). We developed a regional overlap-expression rate (rOER) system with cell identity marker gene panels (ciMGPs) to quantify T cell subtype specificity across pre/post-operative blood, 31 diseases, and in 17 organs. A Treg subtype (Tregfci, FOXP3+CTLA4+IL2RA+) was identified and validated for disease-, organ-, and time-specific characteristics across spatializations, temporalizations, diseases, and prognoses. Tregfci was prominently enriched in pre-operative blood and NSCLC tissue but markedly decreased or was absent post-operatively. Spatial transcriptome and multiplex immunostaining revealed that Tregfci localized primarily to the interface between NSCLC and normal tissues, as well as in specific micro-niches. ETS Proto-Oncogene 1 (ETS1) was upregulated in Tregfci, confirmed by knockdown and knockout experiments. ETS1 facilitated Tregfci migration from circulation into tumor tissues via cancer cell-derived chemoattraction. Interactions between ETS1 and Tregfci ciMGPs, and between intracellular organelles, were found to modulate metabolism and mitochondrial function. These findings highlight the importance of Tregfci in understanding the molecular mechanism by which Tregs maintain the balance between systemic and local immune ecosystems. ETS1’s regulation of Tregfci transcriptomic and metabolic profiles were confirmed in human PBMCs treated with an ETS1 inhibitor and in lung tissues from miceETS1-cKO mice. Furthermore, Tregfci and ETS1 represent a distinct molecular signature of T cells and potential therapeutic targets for clinical intervention in lung cancer.