Advances on Anti-Cancer Combination Therapies Targeting DNA Repair Pathway, Epigenetics, Microbiomes and the Immune System

Modern pipelines integrating multi-omics data, chemical libraries, structural biology information and artificial intelligence are currently accelerating drug discovery and precision medicine. Aligned with these advances, the multi-omics profiling technologies enable the identification of unique genetic and epigenetic signatures for stratification of patients based on cancer specific target and vulnerability. Targeted therapies to specific receptor or enzyme mutated or overexpressed often fail because cancer cells can adapt quickly. Tumor cells overgrow driven by new gene mutation and parallel crosstalk of signaling pathways. Patients with cancer and the hereditary syndrome targets such as BRCA1/2, and emerging targets such as ATR, CHK1, WEE1, and POLθ, are hypersensitive to ionizing radiation and PARP inhibitors. Combining synthetic lethality inhibitors, chemotherapy and immunotherapy effectively kill cancer cells by breaking multiple survival signaling pathways. Antibodies to immune checkpoint inhibitors targeting molecules like PD-1, PD-L1, and CTLA-4 can improve survival of patients, though predictive immunotype remains challenging. Emerging pharmacological approaches combining either epigenetic modifiers, oncomicrobiotics or engineered bacteria sequentially convert tumors into a highly antigenic, T cell-inflamed, and checkpoint-responsive tumor, providing a mechanistically grounded framework for next-generation precision immunotherapy. However, large human clinical trials remain necessary to standardize protocols, biomarkers and long-term efficacy. Cancer vaccines have evolved through rational engineering synthetic mRNA encoding tumor-specific antigens or tumor-associated antigens. This will enable the next generation of truly therapeutic and preventive vaccines for many cancers. This review provides a timely synthesis of the basic mechanisms for rational multidrug treatments for cancers.