Microbiota as a modulator of drug response: targeting microbial–drug crosstalk in cancer therapy

In recent years, accumulating evidence has established mechanistic connections between the microbiota and the efficacy of anticancer treatments, encompassing microbial communities residing in the gut, within tumors, and across other tissue sites. Across diverse malignancies, distinct compositional and functional profiles of these microbial ecosystems have been associated with differential responses to chemotherapy, immunotherapy, and targeted agents, as observed in both clinical settings and experimental systems. It is now understood that microbial communities exert influence on drug activity through multiple pathways: they may compromise therapeutic efficacy by metabolic inactivation or structural modification of anticancer compounds, or, conversely, potentiate responses by enhancing tumor cell susceptibility. Furthermore, these communities modulate the tumor immune microenvironment, fostering antitumor immunity through augmented antigen presentation and effector cell function, or constraining immune responses via regulatory networks and immunosuppressive myeloid polarization. The crosstalk between microbial cues and signaling networks in malignant and surrounding stromal tissues is widely thought to influence therapeutic outcomes. Key challenges ahead involve proving causation, elucidating context-dependent mechanisms, and translating patient heterogeneity into robust biomarkers and targeted therapies. Anticancer interventions can reportedly alter microbial community structure and function, with therapy-associated dysbiosis potentially contributing to primary or acquired resistance. Microbiota-directed strategies, including transplantation, defined microbial consortia, targeted delivery systems, and lifestyle interventions, are under investigation, yet challenges remain in establishing causality, ensuring safety, and enabling patient stratification. Collectively, these insights establish a translational framework for rationally designed microbiota‒drug combination strategies aimed at enhancing anticancer therapeutic outcomes.