Jinxin Li, Jiatao Hu, Yiren Yang, Hanzhong Zhang, Ying Liu, Yu Fang, Le Qu, Anqi Lin, Peng Luo, Aimin Jiang, Linhui Wang
Therapeutic resistance remains a defining challenge in oncology, limiting the durability of current therapies and contributing to disease relapse and poor patient outcomes. This review systematically integrates recent progress in understanding the molecular, cellular, and ecological foundations of drug resistance across chemotherapy, targeted therapy, and immunotherapy. We delineate how genetic alterations, epigenetic reprogramming, post-translational modifications, and non-coding RNA networks cooperate with metabolic reprogramming and tumor microenvironment remodeling to sustain resistant phenotypes. The influence of the microbiome is highlighted as an emerging determinant of therapeutic response through immune modulation and metabolic cross-talk. By summarizing key regulatory circuits, We establishe a unified framework linking clonal evolution, metabolic adaptability, and tumor ecological dynamics. We further synthesizes novel therapeutic strategies that convert resistance mechanisms into therapeutic vulnerabilities, including synthetic lethality approaches, metabolic targeting, and disruption of stem cell and stromal niches. Advances in single-cell and spatial omics, liquid biopsy, and artificial intelligence are emphasized as transformative tools for early detection and real-time prediction of resistance evolution. This review also identifies major translational gaps in preclinical modeling and proposes precision oncology frameworks guided by evolutionary principles. By bridging mechanistic understanding with adaptive clinical design, this work provides an integrated roadmap for overcoming therapeutic resistance and achieving sustained, long-term cancer control.