Background: Advances in immunotherapy have had little impact in prostate cancer (PCA). We have previously examined the immune microenvironment in both localized and metastatic PCA and found that primary PCA shows local inflammation/adaptive immunity whereas metastatic disease shows a shift towards immune suppression (Deichaite, 2022). Herein, we examine immune remodeling in PCA by evaluating changes in gene expression between localized and metastatic disease with heterogeneous treatment patterns in both primary and metastatic samples. Methods: Tumors from PCA (N = 5,419) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Samples collected from the prostate gland (N = 3,284) or metastatic sites (N = 2,135) were analyzed. The Mann-Whitney U test was applied as appropriate, with P-values adjusted for multiple comparisons (q< .05). Real-world overall survival (OS) data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations. Survival for tumors with high (-H) and low (-L) expression of genes of interest, defined as top and bottom quartile of expression (transcripts per million, TPM) across all tumors, was investigated. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Results: Compared to metastatic PCA, primary samples had increased median expression of pro-inflammatory genes IL-6 (1.2-fold), SELE (1.9-fold), NRK (6.3-fold), CEBPD (1.2-fold), NFKB2 (1.4-fold) and FOXP3 (1.4-fold) (each q< .05). GSEA identified enrichment of E2F target genes in primary samples, while metastatic samples were enriched in inflammatory response, KRAS signaling and IL2/STAT5 signaling pathways. The expression of inflammatory genes affected OS differently based on site. IL-6, NRK and SELE-H levels in primary samples were associated with increased OS. Within metastatic samples, CEBPD-H was associated with decreased OS and NFKB2-H was associated with an increased OS. FOSB-H was associated with increased OS in both primary and metastatic samples. Conclusions: We identify significant differences in the expression of inflammatory regulators and cytokines between localized and metastatic PCA tumors, which correlate with OS. These changes in the immune microenvironment can be leveraged for rational immunotherapy development and better targeted approaches.