Targeting Microbe-Mediated Macrophage Education: A Novel Paradigm in Cancer Immunotherapy

The tumor microenvironment (TME) is a complex ecosystem where interactions between tumor cells, immune cells, and microbes notably influence cancer progression and response to therapy. Tumor-associated macrophages (TAMs), which are crucial components of the TME, exhibit remarkable plasticity, adapting their functions in response to signals from both the tumor and its microbiota. Microbes-including bacteria, viruses, fungi, and their metabolites-modulate multiple aspects of TAM biology, from polarization and metabolism to immune modulation, thereby influencing tumor progression and immune evasion. This review focuses on the mechanisms through which microbes shape TAM responses, particularly in the context of cancer immunotherapy. Emerging therapeutic strategies leverage these microbe-TAM interactions using engineered microbes, oncolytic viruses, and microbial nanomaterials to reprogram TAMs and enhance antitumor immunity. Although formidable challenges remain, including spatial and temporal heterogeneity, mechanistic complexity, and safety concerns, these innovative approaches hold the potential to revolutionize cancer treatment. By targeting the microbe-TAM axis, this therapeutic strategy offers a promising avenue for overcoming resistance and improving the effectiveness of cancer immunotherapy.