Background: SGLT2 has been identified as being overexpressed in a diverse set of cancers. Retrospective data has demonstrated a correlation between the use of SGLT2 inhibitors and a reduced incidence of lung cancer. We explored the association of SGLT2-coding gene SLC5A2 with the transcriptomic, genomic, immunological landscape and outcomes in a subset of solid tumors. Methods: Breast ([N = 5623], HR+HER2- [6044] or TNBC [3040]), Colorectal carcinoma (CRC, 15425), NSCLC ([21603], Adenocarcinoma [AC, 8180] or Squamous Cell Carcinoma [SCC, 3579]), Pancreatic (Panc: 5488) and Prostate (PC: 5500) tumors were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1+ (22C3: TPS 1% for lung or SP142: 2+, 5% all other), Her2/Neu (+: ≥3+ and > 10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was assessed by IHC. Mutations were defined as pathogenic SNVs/indels (-Mt). SLC5A2-H and -L expression (transcripts per million, TPM) was defined by cancer type as top and bottom quartile, respectively. Cell infiltration was estimated by QuantiSEQ. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate (p < .05, adjusted for multiple comparisons). Real-world overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined patients. Results:SLC5A2 expression varied across cohorts (TNBC: 1.2 TPM, HR+HER2-BC: 1.7, CRC: 2.2, AC: 1.8, SCC: 1.3, Panc: 1.7, PC: 1.7, p < .05). SLC5A2-H had a higher prevalence of FGF3 amplifications in HR+HER2- BC (17.4% -H v 10.4 -L), CRC (1.4 v .45) and PC (4.4 v .89, p < .05 all). KRAS-Mt was more prevalent in SLC5A2-L CRC (41% v 53) as was BRAF-Mt (6 v 14, p < .05 all). There was a lower prevalence of PDL1+ in SLC5A2-H for HR+HER- BC (14% -H v 24 -L), CRC (2 v 6), AC (47 v 68), SCC (50 v 66) and Panc (10 v 19, p < .05 all). All SLC5A2-H tumors had increased Neutrophil, B, NK cell infiltrate (Table) and an increased prevalence of T cell-inflamed tumors (p < .05, all). SLC5A2-H had longer OS v -L in CRC (HR .82 [.76-.88], p <.001), PC (HR .85 [.74-.99], p =.03), HR+HER2- BC (HR .79 [.68-.91], p < .001) and AC (HR .79 [.73-.85], p < .001). Conclusions:SCL5A2-H across all investigated tumors was associated with increased immune infiltrate and a T cell-inflamed phenotype in addition to improved survival in multiple cancer types. Future research on SGLT2 should delineate its role in cancer formation versus its association as a potential positive prognostic marker.