Mechanisms of Chemoresistance in Solid and Hematologic Malignancies: Challenges and Future Perspectives

Chemotherapy is a foundational element in cancer therapy; however, the development of resistance to antineoplastic agents presents a significant challenge to achieving enduring therapeutic triumphs. The acquisition of drug resistance by malignant cells is the result of a complex interplay between inherent and acquired mechanisms. This phenomenon leads to a reduction in pharmacological effectiveness and contributes to treatment failure. This review investigates the primary mechanisms contributing to chemoresistance in specific malignancies, namely lung, pancreatic, and thyroid cancers, along with non-Hodgkin lymphoma. The primary focus of this research is on genetic modifications, interactions within the tumor microenvironment, and cellular adaptations at the molecular level. The present study places particular emphasis on the contributions of drug efflux pumps, DNA repair pathways, epithelial-mesenchymal transition (EMT), microRNAs, and the suppression of apoptosis in mediating this resistance. In addition, we examine promising approaches to counteract drug resistance, encompassing multi-agent regimens, inhibitors targeting specific molecular pathways, and innovative therapeutic modalities. A comprehensive understanding of these fundamental mechanisms is imperative for the development of sophisticated therapeutic interventions that not only improve patient outcomes but also effectively address resistance. The resistance pathways and prospective translational approaches discussed are drawn from both preclinical and clinical investigations, providing a thorough perspective.