The intratumoral microbiome: a review of the tumor microenvironment's fourth axis shaping anti-tumor immunity, cancer prognosis, and therapeutic response.

The tumor microenvironment (TME) is a well-documented, complex, and dynamic ecosystem traditionally considered among three major axes: 1) malignant cells, 2) stromal cells, and 3) infiltrating immune cells; all whose interactions have been assumed to shape tumor growth, progression, and therapeutic response. Specific TME profiles are strongly associated with cancer prognosis, especially those characterized by distinct immune cell populations. Within the TME, less-studied populations of various microorganisms constitute the intratumoral microbiome. While the systemic microbiome is well-established as a regulator of overall health, disease progression, and cancer prognosis, the role of microorganisms residing directly within tumors remains largely underexplored and often overlooked. As evidence on the intratumoral microbiome continues to emerge, it is increasingly apparent that, in addition to the previously characterized components of the TME, these tumor-resident microbes may significantly impact the TME through complex interactions, effectively constituting a fourth component that must be considered alongside malignant, immune, and stromal cells. We therefore propose a framework in which the TME is defined across four axes: malignant cells, stromal cells, infiltrating immune cells, and intratumoral microbes. Herein, we review the effects of intratumoral microbes on various immune cell types commonly studied within the TME, their effects on specific cancers, and subsequent therapeutic insights that arise from understanding the intratumoral microbiome.