The effects of tobacco smoke on breast cancer lung metastasis

Although metastasis is the fatal hallmark of cancer, the mechanisms leading to colonization of disseminated tumor cells (DTCs) remain poorly defined. Growing evidence suggests that the immune microenvironment determines the fate of DTCs. Natural killer (NK) cells with an affinity for DTCs can thus hinder metastatic outgrowth. However, lifestyle risk factors such as tobacco smoking (active or passive) may interfere with immune responses and tip the balance toward a tumor-promoting environment. Although the link between tobacco smoking, skewed immunity and cancer is clear, the cause and the direction of causality, as well as the cellular and molecular mechanisms underpinning smoke-evoked breast cancer lung metastasis are not clear. Here, using single-cell transcriptomic profiling on immune cells, preclinical mouse models, and patient samples, we show that tobacco smoking enriches for CD177hi CD52hi neutrophils, which sustain lung metastases by suppressing NK cell cytotoxicity. Computational analysis and ex vivo functional assays revealed that this suppression relies mechanistically on ANXA1-FPR2 signaling. Thus, ANXA1, which has pro-resolving effects on inflammatory response to insults, fuels metastatic outgrowth during exposure to smoke. These cellular and molecular mechanisms could open new therapeutic options for current smokers with lung metastasis that would benefit from interfering with the ANXA1-FPR2 axis.