Background: Patients with small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and efficacy of available therapies, including immune checkpoint inhibitors (ICI), is limited. Toward developing novel immunomodulatory strategies, we evaluated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP). Methods: Patients with SBNET who underwent surgical resection at MD Anderson Cancer Center from 2003-2016 were retrospectively analyzed. Overall survival (OS) was assessed using the Kaplan-Meier method and Cox proportional hazards model was used for multivariate analysis (MVA). Bulk transcriptional profiling was performed using the Nanostring PanCancer-Immune Panel. DSP was performed with whole human transcriptome using PanCK to segment tumor and adjacent stroma; 88 distinct regions were analyzed using differential gene expression and Reactome pathway enrichment pipelines. Results: Resected SBNETs from 42 patients were selected for transcriptional analysis. Unsupervised clustering of gene expression demonstrated dichotomization into high and low cancer testis antigen (CTA) expression. CTA-high patients (n=12) demonstrated elevated expression of type-I interferons (IFN) and CTAs such as PRAME, GAGE1, and MAGEA3 and had significantly longer OS compared to CTA-low patients (n=30; median OS not reached vs 1975 days, p=0.008). MVA controlling for age, sex, metastatic disease, and Ki-67% confirmed CTA-high status as an independent predictor of longer OS (hazard ratio [HR] 0.2, 95% confidence interval [CI] 0.05-0.83). A pilot DSP experiment with 4 CTA-high and 4 CTA-low tumors revealed higher expression of epigenetic modification genes (e.g., H3C1, H2BC8, p<0.001) in CTA-high tumors with significant enrichment in epigenetic pathways (e.g., histone acetylation, DNA methylation). CTA-high tumors exhibited increased M2 macrophage presence (p=0.025) and increased stromal compartment NK cell activation (p=0.001). Conclusions: High expression of CTA and type-I IFN in resected SBNET is associated with longer survival, agnostic of stage or grade. While CTA expression has been implicated in tumor immunogenicity, this is the first work to identify a clinical signal in SBNET. Increased IFN in CTA-high tumors, corroborated by increased stromal NK cell activation, suggests an immune-mediated component of improved survival. Spatial transcriptomic analysis reveals epigenetic differences in CTA-high tumors and highlights the potential for combination epigenetic modifiers and immunotherapy in future trials.