Simple Summary Growing evidence suggests that the microbiota-or better, the changes in microbiota composition and characteristics-plays a role in lung cancer onset and is associated with each phase of tumor progression. A relevant amount of data are now available and under investigation regarding the characterization of the microbiome associated with lung cancer. However, in some cases, they are redundant, and in many others, hyper specialist and technical. The goal of this review is to summarize and discuss the state of the art regarding the cross-talk between lung tumors and the microbial compartment and also to put into a clinical frame their mutual interaction and influence. This pragmatic approach will be of help for future diagnostic, therapeutic and prognostic purposes. It is well known that lung cancer relies on a number of genes aberrantly expressed because of somatic lesions. Indeed, the lungs, based on their anatomical features, are organs at a high risk of development of extremely heterogeneous tumors due to the exposure to several environmental toxic agents. In this context, the microbiome identifies the whole assemblage of microorganisms present in the lungs, as well as in distant organs, together with their structural elements and metabolites, which actively interact with normal and transformed cells. A relevant amount of data suggest that the microbiota plays a role not only in cancer disease predisposition and risk but also in its initiation and progression, with an impact on patients' prognosis. Here, we discuss the mechanistic insights of the complex interaction between lung cancer and microbiota as a relevant component of the microenvironment, mainly focusing on novel diagnostic and therapeutic objectives.
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