Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells?

Chemotherapeutic drugs kill cancer cells or control their progression all over the patient?s body, while radiation -and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresis-tance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conven-tional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.