LAUSR

Simple Summary Immunotherapy is achieving impressive results in the treatment of several cancers. While the main strategies aim to re-invigorate the specific lymphocyte anti-tumor response, many studies underline that altered myeloid cell frequency and functions can dramatically interfere with the responsiveness to cancer therapies. Therefore, many novel strategies targeting TAMs and MDSCs in combination with classical treatments are under continuous evolution at both pre-clinical and clinical levels, showing encouraging results. Herein, we depict a comprehensive overview of myeloid cell generation and function in a cancer setting, and the most relevant strategies for their targeting that are currently in clinical use or under pre-clinical development. Abstract In recent years, the immune system has emerged as a critical regulator of tumor development, progression and dissemination. Advanced therapeutic approaches targeting immune cells are currently under clinical use and improvement for the treatment of patients affected by advanced malignancies. Among these, anti-PD1/PD-L1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) are the most effective immunotherapeutic drugs at present. In spite of these advances, great variability in responses to therapy exists among patients, probably due to the heterogeneity of both cancer cells and immune responses, which manifest in diverse forms in the tumor microenvironment (TME). The variability of the immune profile within TME and its prognostic significance largely depend on the frequency of the infiltrating myeloid cells, which often represent the predominant population, characterized by high phenotypic heterogeneity. The generation of heterogeneous myeloid populations endowed with tumor-promoting activities is typically promoted by growing tumors, indicating the sequential levels of myeloid reprogramming as possible antitumor targets. This work reviews the current knowledge on the events governing protumoral myelopoiesis, analyzing the mechanisms that drive the expansion of major myeloid subsets, as well as their functional properties, and highlighting recent translational strategies for clinical developments.