In recent decades, immune dysregulation has emerged as a leading factor in the pathogenesis of myelodysplastic neoplasms (MDS) and myeloproliferative neoplasms (MPN), in addition to somatic mutations. Beyond commonly used immunotherapies (e.g., haematopoietic stem cell transplantation, immunosuppressive therapy, interferon-alpha and lenalidomide), many strategies targeting the immune system are currently under evaluation, such as increasing tumour cell elimination via T cells targeting antigens with cell-mediated inhibition or costimulatory signals, stimulating macrophage-mediated tumour elimination, or reducing immunosuppression driven by myeloid-derived suppressor cells. Interesting results were obtained with drugs targeting the crosstalk between tumour cells and macrophages and the immune checkpoint inhibitors, particularly when combined with hypomethylating agents. However, this approach is not convincing overall and is unlikely to change clinical practice in the near future. One reason is related to a non-classic tumour microenvironment in “liquid” haematologic malignancies, which, unlike in solid tumours, has easier accessibility to the most immunogenic malignant clones with subsequent elimination by immune cells. Furthermore, immune system dysregulation is highly heterogeneous within the same type of disease both because it is influenced by somatic mutation type and the grade of inflammation and because it dynamically changes during disease progression. Therefore, the most effective approach to immune therapy is to characterise each patient’s disease thoroughly. This can be done by integrating information about the mutational status, the type and grade of immune system disruption, and the other extrinsic players in disease pathogenesis like the microbiome, inflammation, and bone marrow niche. A comprehensive and multifactorial ‘immune-scoring’ system will result in more robust patient stratification and will help to identify the most suitable immunotherapy for each patient.

(BELG J HEMATOL 2023;14(3):105–13)