Metronomic Chemotherapy: Anti-Tumor Pathways and Combination with Immune Checkpoint Inhibitors.

Increasing evidence pinpoints metronomic chemotherapy, a frequent and low dose drug administration with no prolonged drug-free intervals, as a potential tool to fight certain types of cancers. The primary identified targets of metronomic chemotherapy were the tumor endothelial cells involved in angiogenesis. After this, metronomic chemotherapy has been shown to efficiently target the heterogeneous population of tumor cells and, more importantly, elicit the innate and adaptive immune system reverting the "cold" to "hot" tumor immunologic phenotype. Although metronomic chemotherapy is primarily used in the context of a palliative setting, with the development of new immunotherapeutic drugs, a synergistic therapeutic role of the combined metronomic chemotherapy and immune checkpoint inhibitors has emerged at both the preclinical and clinical levels. However, some aspects, such as the dose and the most effective scheduling, still remain unknown and need further investigation. Here, we summarize what is currently known of the underlying anti-tumor effects of the metronomic chemotherapy, the importance of the optimal therapeutic dose and time-exposure, and the potential therapeutic effect of the combined administration of metronomic chemotherapy with checkpoint inhibitors in preclinical and clinical settings.