Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms capable of a wide range of infections that primarily involve the lymphatic system and the lower respiratory tract. In recent years, cases of lung infection sustained by NTM have been steadily increasing, due mainly to the ageing of the population with underlying lung disease, the enlargement of the cohort of patients undergoing immunosuppressive medications and the improvement in microbiologic diagnostic techniques. However, only a small proportion of individuals at risk ultimately develop the disease due to reasons that are not fully understood. A better understanding of the pathophysiology of NTM pulmonary disease is the key to the development of better diagnostic tools and therapeutic targets for anti-mycobacterial therapy. In this review, we cover the various types of interactions between NTM and lymphoid effectors of innate and adaptive immunity. We also give a brief look into the mechanism of immune exhaustion, a phenomenon of immune dysfunction originally reported for chronic viral infections and cancer, but recently also observed in the setting of mycobacterial diseases. We try to set the scene to postulate that a better knowledge of immune exhaustion can play a crucial role in establishing prognostic/predictive factors and enabling a broader investigation of immune-modulatory drugs in the experimental treatment of NTM pulmonary disease.

Immune checkpoint inhibitors (ICIs) are drugs growingly employed in the treatment of cancers but there are still uncertainties about their possible role in the risk of developing non-tuberculous mycobacteria (NTM) infections.To understand this, we performed a systematic review of the literature including studies published between 20/06/2012–20/06/2022 which described the occurrence of NTM infections among patients treated with ICIs.Overall, we included 7 studies describing 9 patients with NTM infection occurring during ICIs therapy.NTM infections occurring during ICIs therapy are mainly caused by germs belonging to theMycobacterium avium complex, involve primarily the lungs, on average 1 year after the start of treatment and are not associated with immunosuppressive treatments.

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