The Intratumor Microbiome: An Untapped Avenue for Translational Applications in Cancer Immunotherapeutics

The human body harbors distinct microbial communities at each body site. One microbial niche of particular interest within the human body is the tumor microenvironment. These intratumor microbes are linked to tumor initiation, progression, and metastasis through diverse mechanisms, including activation of oncogenic pathways and modulation of antitumor immunity. Recent studies have emphasized the role of intratumor microbes in influencing the response and outcome of cancer immunotherapeutics and vaccines. Further data suggest a crucial role of microbial metabolites in the metabolic rewiring of CD8+ T cells controlling antitumor immunity. This knowledge is vital to promote our understanding of the role of microbes in the tumor microenvironment and advance translational applications. In this review, we discuss factors that shape the structure of the intratumor microbiome, such as the translocation of gut microbes and the development of local microbial communities. This study highlights the remote control of gut microbes in the tumor microenvironment, disease progression, and therapy outcome. We detail interactions of intratumor microbes and their crosstalk with tumor and immune cells, such as tissue-resident and tumor-infiltrating T cells. We discuss open research questions in this field, including defining oncomicrobiotics, the subset of microbiota with biotherapeutic potential in inducing antitumor immunity. We highlight challenges and opportunities, emphasizing the future direction of developing next-generation engineered probiotics that can advance delivery, maximize the efficacy of cancer therapy, or even serve as a non-invasive technique to sense and detect tumor cells.