Multidrug resistance in cancer: current understandings and future perspective

Multidrug resistance (MDR) remains the core clinical barrier limiting the achievement of durable and effective treatment for various tumors. With the deepening of understanding, MDR has been redefined from the traditional, static "drug efflux" model to a systemically adaptive survival strategy driven by highly heterogeneous tumor populations under therapeutic pressure, characterized by dynamic evolution. This complex phenotype arises from the deep intertwining and synergistic action of multi-layered survival networks. Herein, this review systematically delineates the evolution and multidimensional remodeling of the underlying mechanisms of MDR. We comprehensively outline the cell-intrinsic, autonomous resistance mechanisms of tumor cells, including intracellular drug redistribution and evasion of non-apoptotic cell death pathways. Concurrently, we summarize the tumor microenvironment (TME)-mediated, non-autonomous resistance mechanisms, such as physical barriers formed by stromal cells, intercellular communication networks, and the establishment of a profoundly immunosuppressive microenvironment. Building on this foundation, the review critically assesses the current drug resistance dilemmas faced by various therapeutic modalities and refractory cancer types. It focuses on discussing novel, precision reversal strategies targeting MDR, including nanotechnology-based delivery systems, single-cell and spatial omics analysis, and artificial intelligence (AI) large model-driven predictive and interventional systems. Furthermore, this review explores the underlying reasons for the repeated clinical failures of traditional single-target interventions. It outlines a direction for future translational research: a paradigm shift from "singular target killing" to "multidimensional ecological remodeling," advancing towards a closed-loop, personalized precision therapy framework based on dynamic monitoring and multi-target synergistic intervention.