Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

SIMPLE SUMMARY: Metronomic chemotherapy with different mechanisms of action against cancer cells and their microenvironment represents an exceptional holistic cancer treatment. Each type of tumor has its own characteristics, including each individual tumor in each patient. Understanding the complexity of the dynamic interactions that take place between tumor and stromal cells and the microenvironment in tumor progression and metastases, as well as the response of the host and the tumor itself to anticancer therapy, will allow therapeutic actions with long-lasting effects to be implemented using metronomic regimens. This study aims to highlight the complexity of cellular interactions in the tumor microenvironment and summarize some of the preclinical and clinical results that explain the multimodality of metronomic therapy, which, together with its low toxicity, supports an inhibitory effect on the primary tumor and metastases. We also highlight the possible use of nano-therapeutic agents as good partners for metronomic chemotherapy. ABSTRACT: The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.