Inflammation plays a central role in cancer progression, with emerging evidence highlighting the intricate interplay between the host microbiome and inflammatory processes. This dynamic relationship drives cancer development through transcriptional regulation and metabolic dysregulation, while also influencing treatment responses. Despite significant advances, most metagenomic studies have centered on the gut microbiome, largely overlooking the tumor-specific microbiome and its impact on genomic and epigenetic alterations. This knowledge gap is particularly evident in inflammation-prone cancers such as prostate and bladder cancers, where the presence and function of tumor-specific microbial populations remain poorly understood. To address these challenges, we hypothesize that the tumor microbiome constitutes a critical component of the tumor microenvironment, contributing to cancer progression at transcriptional, genomic, and epigenetic levels. Leveraging unique clinical cohorts from Sweden and international collaborations, we aim to assess the impact of tumor-microbial diversity on cancer progression, characterize metabolic and transcriptional dysregulation across genitourinary cancers, and explore the potential of tumor-microbial abundance as a prognostic biomarker. Furthermore, we will investigate whether the presence of a tumor microbiome is a universal feature of the tumor microenvironment, including in cancers distant from microbial ecosystems such as glioblastoma. Lastly, we will elucidate how the tumor microbiome induces genomic mutations and epigenetic changes, with downstream effects on gene expression. By integrating advanced computational strategies with multi-omics approaches, this research will establish the tumor microbiome as a pivotal factor in cancer biology, providing new insights into its role in disease progression and offering innovative avenues for precision medicine.