Dose-dependent M2 macrophage polarization induced by Talaromyces marneffei promotes lung cancer cell growth via arginine-ornithine-cycle activation.

It is now widely accepted that lungs are colonized by diverse microbes. Dysbiosis of the lung microbiota has been found to affect the progression of lung cancer. Fungi are a major component of the lung microbiota. However, the causal links between the mycobiome or specific species and lung cancer remain unclear. To address this, we conducted a study examining the composition of lung mycobiota in Non-Small-Cell Lung Cancer (NSCLC) patients using shotgun metagenomics. The differential taxa between NSCLC patients and non-cancer controls were defined by the Wilcoxon rank-sum test. Nested PCR was used to measure the abundance of specific fungal species. Metabolomics analysis was performed to investigate the metabolic reprogramming of macrophages triggered by intracellular infection of specific fungal species. In vitro and in vivo assays were conducted to examine the effect of the specific fungus on cancer cell growth. Our findings showed that Ascomycota, Microsporidia and Mucoromycota were the dominant fungal taxa in the lungs. Talaromyces marneffei (T.marneffei) was the most significantly differential fungus between lung cancer patients and non-cancer controls, with its abundance positively correlated with lung cancer. The lung cancer animal model demonstrated that T.marneffei promotes lung cancer growth. Our study also demonstrated that T.marneffei promotes lung cancer cell growth by inducing dose-dependent M2 macrophage polarization through arginine-ornithine-cycle activation. Furthermore, inhibition of arginase can reduce M2 polarization of macrophages and the survival of T. marneffei inside macrophages. In summary, our study reveals that the increased abundance of T. marneffei in the lungs affects lung cancer cell growth by triggering arginine-induced M2 polarization of macrophages. These findings provide potential drug targets for the development of therapies aimed at targeting the survival of fungi inside macrophages in the fight against cancer.