Simple SummaryMetronomic chemotherapy, a continuous administration of a lowered dose of drugs without long breaks, is currently considered an alternative approach for the treatment of cancer patients experiencing drug resistance and/or toxic side effects. This therapy can lead to tumor control by inhibiting tumor angiogenesis, suppressing tumor cell growth, and indirectly boosting the anti-tumor immune response. A synergic therapeutic role was observed after the combined administration of metronomic chemotherapy and immune checkpoint inhibitors, in both preclinical and clinical settings. However, the optimal drug combinations, sequence, and optimal concentration–time factors should be evaluated in representative preclinical models. Here, we report the current knowledge of the underlying mechanisms of action of metronomic chemotherapy and the potential therapeutic effect when administered in combination with the immune checkpoint inhibitors, at both preclinical and clinical levels.AbstractIncreasing 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.