Targeting the intratumoral microbiota to overcome cancer immunotherapy resistance

Abstract Cancer remains a significant global health threat. The tumor microenvironment (TME) is a sophisticated ecological niche that exerts a pivotal effect on treatment outcomes. Among the diverse components composing the TME, the intratumoral microbiota (IM) has become a research focus, which can regulate tumor initiation, progression, and therapeutic response. The link between cancer and microorganisms dates back 4000 years. Advanced sequencing technologies have revealed that the unique microbial communities within tumors serve a dual function: directly modulating tumor cell biology via metabolic processes and shaping TME immunity through interactions with immune and matrix components. Their metabolites act as mediators either inducing immunosuppression via immune metabolic reprogramming or triggering systemic immunity through pattern recognition receptors. Consequently, IM imbalances may contribute to immune evasion and therapeutic resistance. This article addresses immunotherapy resistance and treatment failure, systematically exploring the origins and detection methods of IM, elucidating its regulatory mechanisms within the TME, examining its impact on immunotherapy efficacy, assessing the utility of IM in diagnostic biomarker applications, and discussing the technical challenges and a roadmap for further inquiry, directed toward providing a comprehensive framework to advance precision immunotherapy in cancer treatment.