Single-Cell Genetic Architecture Identifies GSTM1 as a Novel Therapeutic Target for Reversing T-Cell Ferroptosis in NSCLC

Background Ferroptosis has emerged as a pivotal mechanism in cancer surveillance, particularly in determining the efficacy of immunotherapy. However, the precise genetic switches that regulate ferroptosis sensitivity within specific immune cell lineages remain poorly characterized due to the resolution limits of bulk tissue analysis. Methods To address this, we constructed a high-resolution genetic map of ferroptosis in non-small cell lung cancer (NSCLC). We applied a multi-stage integrative framework, harmonizing single-cell expression quantitative trait loci (sc-eQTL) from 14 immune cell populations with large-scale genomic data from the FinnGen cohort (N = 385,195). Results Our analysis identified 40 putative causal genes driving NSCLC susceptibility. A key finding is that GSTM1 expression in CD8 + naive T cells confers a robust protective effect (OR = 0.60, P = 2.17 x 10^-4). Multi-omic validation indicates that GSTM1 functions as a "metabolic shield," enhancing T-cell functional quality rather than simple infiltration density. Furthermore, we reveal a striking cell-state-dependent antagonism for MAPK3, which acts as a protective factor in the naive state (OR = 0.67) but switches to a risk-promoting factor in effector CD4 + T cells (OR = 1.39). Conclusions This study uncovers a lineage-specific genetic architecture of ferroptosis, highlighting GSTM1 and MAPK3 as critical regulators of T-cell metabolic fitness. These findings suggest that stratifying patients based on GSTM1 status could serve as a novel strategy to guide precision immunotherapy.