Background: Retrospective data suggest that SGLT2 inhibitors, commonly used in diabetes, are associated with a lower incidence of cancer development and in vivo data indicate SGLT2 plays a role in the development of NSCLC. We investigated the genomic and immunological landscape of NSCLC [adenocarcinoma (AC) or squamous cell carcinoma (SCC) histology] with high and low expression of the SGLT2-coding gene SLC5A2 and the relationship with clinical outcomes. Methods: NSCLC tumors of AC (N = 11,725) or SCC (N = 4,158) histology were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1 expression (22C3; Positive (+): TPS ≥1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations/MB. Mutations were defined as pathogenic SNVs/indels. SLC5A2-H and -L expression (transcripts per million) was defined as top and bottom quartile, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate, with P-values adjusted for multiple comparisons (p < .05). Real-world overall survival (OS) data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients (N = 13,505). Results: In AC tumors, SLC5A2-H was associated with higher rates of EGFR (20.8 vs 13.5%, p< .05) and STK11 mutations (20.1 vs 12.9%, p< .05), but lower rates of TP53 (50.8 vs 69.5%, p< .05) and ARID1A (8.7 vs 4.6%, p< .05) mutations. There was no significant difference in the KRAS mutation rate (35.6 vs 37.1%, p = 1). AC and SCC SLC5A2-H tumors had a lower prevalence of PD-L1+ (AC: 47 vs 68%, SCC: 50 vs 67%, p< .05). AC SLC5A2-H tumors had a lower prevalence of TMB-H (30 vs 39%, p< .05), but not in SCC (40 vs 41%, p = .6). SLC5A2-H tumors were associated with a higher prevalence of T cell-inflamed tumors (AC: 40 vs 19%, SCC: 33 vs 11%, p< .05). SLC5A2-H AC had longer OS as compared to SLC5A2-L AC tumors (HR = 0.787 [.73-.85], p< .001) but no significant difference in time on treatment (TOT) with pembrolizumab was observed (HR .90 [.78-1.03], p = .13). SLC5A2-H SCC tumors had significantly longer OS (HR .88, [.78-1.00], p = .045) and they had significantly longer TOT with pembrolizumab (HR .72 [.56-.94], p = .01). Finally, SLC5A2-H, KRAS mutant AC tumors had significantly longer OS (HR .64 [.57-.73], p < .001) whereas SLC5A2-H KRAS mutant SCC tumors (HR 1.46 [.83-2.57], p = .19) trended towards shorter OS. Conclusions:SLC5A2 expression was associated with a highly altered genomic landscape in AC. In specific mutational and histological subgroups, differences in SLC5A2 expression were associated with OS and responsiveness to immunotherapy. These mutational and histological subtypes should be further investigated as research on SGLT2 inhibitors progresses.