Spatial Heterogeneity of Intratumoral Microbiota: A New Frontier in Cancer Immunotherapy Resistance Original paper

What was studied?

This review article focuses on the spatial heterogeneity of intratumoral microbiota and its role in cancer immunotherapy resistance. It explores how microbial communities within tumors are unevenly distributed across different tumor regions, influencing immune responses, tumor progression, and therapeutic resistance. The study investigates how variations in microbial composition, metabolic products, and immune interactions within different regions of the tumor microenvironment (TME) contribute to differential responses to immunotherapy. It emphasizes the importance of understanding the spatial distribution of intratumoral microbiota for developing novel therapeutic strategies to overcome resistance to immunotherapy, particularly immune checkpoint inhibitors.

Who was studied?

The article reviews data from clinical and preclinical studies investigating intratumoral microbiota in various cancer types, including colorectal, breast, pancreatic, and oral cancers. The studies highlighted the presence of specific microbial species in different tumor regions, their interaction with immune cells, and their impact on cancer progression and treatment outcomes. These studies include investigations on how bacterial, fungal, and viral populations within the TME are influenced by tumor-specific factors, such as vascularity, hypoxia, and immune cell infiltration. The research also examines the implications of microbial spatial heterogeneity on therapeutic responses, particularly focusing on immune checkpoint inhibitors and chemotherapy.

Most important findings

The review highlights several key findings related to the spatial heterogeneity of intratumoral microbiota. It identifies how microbial communities differ significantly between various regions of the tumor, such as the tumor core, invasive margins, and immune-exclusion zones. This heterogeneity is influenced by factors like tumor anatomy, local immune status, and treatment interventions. Specific bacteria, such as Fusobacterium nucleatum, Bacteroides fragilis, and Malassezia, were found to be enriched in certain tumor areas, influencing immune cell infiltration and immune checkpoint expression. For instance, Fusobacterium nucleatum is shown to thrive in hypoxic regions of colorectal cancer, where it contributes to immune evasion by interacting with immune cells like T cells and myeloid-derived suppressor cells (MDSCs). Additionally, microbial metabolites, such as short-chain fatty acids and lactate, establish spatial gradients within tumors that affect immune cell function and contribute to therapeutic resistance. These findings suggest that the spatial distribution of microbiota within tumors can significantly modulate immune responses and impact the efficacy of immunotherapy.

Key implications

The findings of this review underscore the potential of targeting the spatial heterogeneity of intratumoral microbiota to improve cancer treatment outcomes. By understanding the microbial composition and spatial distribution within the TME, clinicians could develop more personalized and precise treatment strategies, potentially enhancing the effectiveness of immunotherapy. The review suggests that therapeutic interventions targeting the microbiota, such as engineered bacteria, probiotics, or bacteriophage therapy, could help reshape the TME and overcome resistance to immune checkpoint inhibitors. However, challenges remain in developing strategies to precisely manipulate microbial populations within tumors, as well as in understanding the full range of microbial interactions and their impact on tumor progression and immune responses. Further research is needed to refine these approaches and explore their clinical applicability.