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Tumor-infiltrating microbes are emerging as a novel dimension of cancer biology, with growing evidence suggesting their potential as prognostic and predictive biomarkers. In this issue, Chen et al demonstrate associations between microbial signatures and treatment response in triple-negative breast cancer (TNBC). They join a growing list of examples whereby tumor-infiltrating microbes influence therapeutic efficacy, with mechanisms ranging from drug metabolism to immune modulation. Here, we explore the known mechanisms, as well as the methodological and conceptual challenges facing microbial biomarker research, including contamination risk, detection sensitivity, and the functional validation of microbial activity. As the field advances, integrating microbial profiling with genomic and immunological data, alongside foundational microbiological techniques, will be essential to clarify the role of microbes in cancer progression and treatment response. Ultimately, a deeper understanding of these microbial ecosystems may open new avenues for precision oncology in TNBC and beyond.