Background <p>Although ion homeostasis in tumor development and treatment has drawn researchers’ attention, its prognostic role in lung adenocarcinoma (LUAD) remains unclear.</p> Methods <p>Differentially expressed genes (DEGs) between normal and LUAD samples (from The Cancer Genome Atlas cohort) were intersected with ion homeostasis-related genes (IHRGs) to yield differentially expressed IHRGs (DE-IHRGs). DE-IHRGs were screened by univariate, LASSO, and multivariate Cox regression to select signature genes and construct a predictive model. Two independent datasets (GSE72094 and GSE26939) were used for validation. Patients were dichotomized by the median ion homeostasis-related risk score (IHRS) into high- and low-IHRS groups, which were subjected to immune infiltration, tumor mutation, and drug sensitivity analyses. The expression of biomarker genes (SFXN1, GRIK2, C7, F2, RHCG) in LUAD cells was detected by qRT-PCR. In an SFXN1 knockdown cell model, the expression of the immune checkpoint protein PD-L1 was assessed by Western blot. In a co-culture system, the effects of SFXN1 on the cytotoxicity and proliferative capacity of CD8⁺ T cells were evaluated.</p> Results <p>A prognostic risk model was established using 15 ion homeostasis-related signature genes (SFXN1, RIC3, KCNK3, GRIK2, CFTR, F2RL1, ATP1A2, C7, F2, CPS1, EPB42, ATP6V0A4, CD52, SCN7A, and RHCG). Immune infiltration analysis revealed higher levels of immune cell infiltration, including B cells, mast cells, neutrophils, and macrophages, in the low-IHRS group. The high-IHRS group exhibited significantly higher tumor mutational burden and higher sensitivity to AZD6738, Docetaxel, and Savolitinib; the low-IHRS group showed greater sensitivity to Axitinib, BMS-754807, and MK-2206. In LUAD cells, SFXN1, GRIK2, F2, and RHCG were significantly upregulated, and C7 was downregulated. Functionally, SFXN1 knockdown suppressed PD-L1 expression and synergistically enhanced the cytotoxicity and proliferation of CD8⁺ T cells.</p> Conclusion <p>The established ion homeostasis-related prognostic model may assist in personalizing treatment strategies and predicting overall survival for LUAD.</p>