Advanced spatial analysis reveals that bacteria living directly within tumors—distinct from gut microbiota—actively modify cancer cell genomic stability, metabolism, and signaling pathways while reshaping the surrounding immune landscape. This intratumoral microbiota (ITM) varies dramatically across cancer types and influences how tumors respond to treatments. The bacterial colonization of tumors represents a paradigm shift from viewing cancer as purely a human cellular disease to understanding it as a complex ecosystem. Unlike systemic microbiome effects, these resident tumor bacteria create localized molecular changes that could explain why identical cancers respond differently to the same treatments. The therapeutic implications are profound: targeted antibiotic strategies, engineered bacterial therapies, and phage treatments could potentially reprogram tumor behavior. However, the field faces significant technical hurdles including extremely low bacterial numbers within tumors, contamination issues, and the challenge of distinguishing causation from correlation. This emerging understanding positions intratumoral bacteria as potential biomarkers for treatment stratification and opens entirely new therapeutic avenues, though rigorous validation in human studies remains the critical next step.