Microbial modulation as a game changer: Boosting immunotherapy efficacy in breast cancer

Breast cancer is generally regarded as an immunologically cold tumor, characterized by limited T cell infiltration and poor responsiveness to immune checkpoint inhibitors. Increasing evidence suggests that the human microbiome, including both gut and tumor-associated microbial communities, serves as a critical regulator of systemic and local antitumor immunity, with potential to convert inert tumors into immune-responsive states. Gut microbiota influence systemic immune homeostasis through metabolites such as lipids, lactic acid, and trimethylamine N-oxide, which modulate T lymphocytes, dendritic cells, leukocytes, and stromal components. Tumor-resident microbiota further shape the tumor immune microenvironment by regulating CD4⁺ and CD8⁺ T cells, NKT cells, Tregs, and macrophages, thereby impacting the efficacy of immune checkpoint blockade. Emerging strategies to sensitize cold breast tumors through microbiome modulation include dietary phytochemicals, bariatric surgery induced microbial shifts, probiotics and postbiotics, polyvalent microbial antigen vaccines, and nanotechnology-based platforms. Clinical challenges remain, particularly interindividual microbial heterogeneity, safety and regulatory considerations, and the need for reliable microbial and immune biomarkers. This review summarizes current advances in microbiota-immune interactions in breast cancer and discusses opportunities for microbiome-targeted strategies to enhance immunotherapy outcomes.