Introduction:
Cancer is a heterogeneous and highly complex disease that annually claims the lives of millions of people, making it one of the leading causes of death worldwide [1]. The number of deaths caused by cancer is growing increasingly and predictions indicate that it will continue to do so. Estimates show that in 2018, 9.6 million cancer-related deaths occurred [2]. However, by 2030, it is projected that around 30 million people may die annually from cancer [2]. That is why cancer is a very serious challenge for public health worldwide, and it becomes increasingly widespread and severe every year. Although there are innovative and diverse methods for cancer treatment, four treatment methods are conventional and usually employed to combat cancer, including surgery, radiation therapy, immunotherapy, and chemotherapy. Chemotherapy, however, faces many challenges such as non-specific targeting of cancer cells, treatment resistance, and cancer recurrence even after successful treatment. The use of targeted small-molecule drugs is one of the ways to improve the outcome of chemotherapy. Because of their low molecular weight (<1000 Da) and small size, they can bind to various targets outside and inside the cell [3]. Since 2001, when the first small molecule tyrosine kinase inhibitor (TKI) drug, imatinib, by the US Food and Drug Administration (FDA), was approved for clinical use, more than 80 small molecule drugs for cancer treatment have been approved by the US FDA and the National Medical Products Administration (NMPA) of China [4]. However, the therapeutic results of targeted small molecules are limited. Cancer cells use a variety of factors and strategies to fight and resist chemotherapy. For this reason, to improve the results of treatments based on small molecules as adjunctive therapy to overcome the challenges of chemotherapy, knowledge and deep understanding of chemotherapy resistance mechanisms and then determining the most effective and main factors as targets for small molecules is very crucial and important. In this study, most of these factors and mechanisms are comprehensively examined in four titles including tumor microenvironment, immunomodulation, DNA repair mechanisms, and cancer stem cells. It is crucial and essential for drug designers and scientists to extensively investigate these mechanisms for the proper and effective design of targeted small molecule drugs as adjunctive chemotherapy treatments.