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Emerging evidence supports the important role of the tumor microbiome in oncogenesis, cancer immune phenotype, cancer progression, and treatment outcomes in many malignancies. In this study, we investigated the metastatic melanoma tumor microbiome and potential roles in association with clinical outcomes, such as survival, in patients with metastatic disease treated with immune checkpoint inhibitors (ICIs). Baseline tumor samples were collected from 71 patients with metastatic melanoma before treatment with ICIs. Bulk RNA-seq was conducted on the formalin-fixed paraffin-embedded (FFPE) tumor samples. Durable clinical benefit (primary clinical endpoint) following ICIs was defined as overall survival ≥24 months and no change to the primary drug regimen (responders). We processed RNA-seq reads to carefully identify exogenous sequences using the {exotic} tool. The 71 patients with metastatic melanoma ranged in age from 24 to 83 years, 59% were male, and 55% survived >24 months following the initiation of ICI treatment. Exogenous taxa were identified in the tumor RNA-seq, including bacteria, fungi, and viruses. We found differences in gene expression and microbe abundances in immunotherapy responsive versus non-responsive tumors. Responders showed significant enrichment of several microbes including Fusobacterium nucleatum, and non-responders showed enrichment of fungi, as well as several bacteria. These microbes correlated with immune-related gene expression signatures. Finally, we found that models for predicting prolonged survival with immunotherapy using both microbe abundances and gene expression outperformed models using either dataset alone. Our findings warrant further investigation and potentially support therapeutic strategies to modify the tumor microbiome in order to improve treatment outcomes with ICIs., Competing Interests: Conflicts of Interest AAT: Contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec. Personal consultant/advisory board fees from Bristol Myers Squibb, Merck, Easai, Instil Bio Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work. EAS: Astellas/Medivation: research support (clinical trial); Johnson & Johnson: advisory board; Merck: advisory board; Vyriad: advisory board; Aura Biosciences: data safety monitoring board CC: None related to this project. Other unrelated projects and clinical trials (research support from Checkmate Pharmaceuticals, Regeneron, Angiodynamics, Optimum Therapeutics) YZ: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD Serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development Consultant honorarium: Pfizer, Novartis JC: Roche/Genentech CEW, SC, RH, LD, MC, ND, RDD, SH, MH, API, NJ, QM, MM, AEGO, LAR, GT, CMU, DS, ACT: None to report

Evidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10-20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors., Competing Interests: CONFLICTS OF INTEREST Carlos Chan: None related to this project. Other unrelated projects and clinical trials (Research support from Checkmate Pharmaceuticals, Regeneron, Angiodynamics, Optimum Therapeutics) Yousef Zakharia: Advisory Board: Bristol Myers Squibb, Amgen, Roche Diagnostics, Novartis, Janssen, Eisai, Exelixis, Castle Bioscience, Genzyme Corporation, Astrazeneca, Array, Bayer, Pfizer, Clovis, EMD serono, Myovant. Grant/research support from: Institution clinical trial support from NewLink Genetics, Pfizer, Exelixis, Eisai. DSMC: Janssen Research and Development Consultant honorarium: Pfizer, Novartis Ahmad Tarhini: Contracted research grants with institution from Bristol Myers Squib, Genentech-Roche, Regeneron, Sanofi-Genzyme, Nektar, Clinigen, Merck, Acrotech, Pfizer, Checkmate, OncoSec. Personal consultant/advisory board fees from Bristol Myers Squibb, Merck, Easai, Instil Bio Clinigin, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca outside the submitted work. Eric Singer: Astellas/Medivation: research support (clinical trial); Johnson & Johnson: advisory board; Merck: advisory board; Vyriad: advisory board; Aura Biosciences: data safety monitoring board Gregory Riedlinger: AstraZeneca advisory board Bryan Schneider: Genentech-Research support (drug supply only); Pfizer-Research support (Drug supply only); Foundation Medicine-research support (sequencing support)