Metabolic Adaptation in Cancer Drug Resistance: Mechanisms and Therapeutic Opportunities

Cancer cells exhibit profound metabolic plasticity that enables them to survive and proliferate under therapeutic pressure. Increasing evidence shows that metabolic reprogramming is not merely a byproduct of oncogenic transformation but a key driver of drug resistance across diverse cancer types. Alterations in glycolysis, mitochondrial metabolism, lipid and amino acid utilization, and redox balance allow tumor cells to adapt to cytotoxic, targeted, and immunotherapies. In parallel, the tumor microenvironment -including hypoxia, nutrient limitation, and stromal interactions- further shapes metabolic states that promote therapeutic failure. Understanding how these metabolic adaptations emerge and are sustained is essential for overcoming resistance and improving clinical outcomes.This Research Topic aims to provide a comprehensive and mechanistic understanding of how metabolic adaptation contributes to cancer drug resistance and to highlight emerging therapeutic strategies that target these processes. We seek to bridge basic, translational, and clinical research by integrating insights into metabolic rewiring with actionable approaches for therapy. Ultimately, this collection will identify vulnerabilities in cancer metabolism that can be exploited to overcome resistance and enhance treatment efficacy.We welcome original research articles, reviews, and perspectives addressing, but not limited to, the following themes:- Mechanisms of metabolic reprogramming underlying resistance to chemotherapy, targeted therapy, radiotherapy, and immunotherapy- Alterations in glycolysis, mitochondrial function, lipid metabolism, amino acid metabolism, and redox homeostasis in resistant tumors- Role of oncogenic signaling pathways (e.g., KRAS, MYC, HIF, mTOR/AMPK) in regulating metabolic adaptation and therapy resistance- Tumor microenvironment-driven metabolic changes, including hypoxia, acidosis, and metabolic crosstalk with stromal and immune cells- Immunometabolism and its role in modulating response and resistance to immunotherapies- Identification and validation of metabolic biomarkers predicting therapy response or resistance- Therapeutic targeting of cancer metabolism, including novel agents, combination strategies, and drug repurposing approaches- Spatial, single-cell, and flux-based approaches to study metabolic heterogeneity in resistant cancers- Diet and systemic metabolic interventions influencing therapy responseSubmissions should provide mechanistic insight and, where applicable, experimental validation. Studies integrating multi-omics or computational approaches are encouraged when supported by robust biological validation and a clear link to cancer metabolism. Purely descriptive or computational studies without experimental validation are not within the scope of this collection. Contributions spanning basic, translational, and clinical research are encouraged, particularly those proposing innovative therapeutic strategies or identifying actionable metabolic vulnerabilities. Topic editors: Venkateshwar G Keshamouni, Aramati Reddy, Rama Krishna Kancha Source: https://www.frontiersin.org/research-topics/80652/metabolic-adaptation-in-cancer-drug-resistance-mechanisms-and-therapeutic-opportunities