Acquired resistance of cancer therapies: Mechanisms and perspectives

Over the past decades, significant progress has been made in cancer treatment, including chemotherapy, targeted therapy, and more recently, immunotherapy. However, only a limited number of patients achieve cure with these therapies. A major challenge lies in acquired resistance to cancer treatments, where patients initially respond but eventually develop resistance and relapse. The underlying mechanisms of acquired resistance are still emerging, encompassing both tumor cell-intrinsic and extrinsic factors, such as the selection of pre-existing resistant clones, acquired genetic mutations, and alterations in the tumor microenvironment. In recent years, several new concepts and significant advances have emerged in this field, such as epigenetic alterations, lineage plasticity, metabolic reprogramming, and cellular crosstalk and signaling within the tumor microenvironment. This review systematically summarizes these advances, aiming to provide a comprehensive theoretical framework that integrates emerging concepts of resistance, while also offering a translational perspective focused on identifying actionable therapeutic targets and guiding the development of next-generation combination strategies to prevent or overcome acquired resistance in the clinic.