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Histidine catabolism is a major determinant of methotrexate sensitivity (vol 559 2021)

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1 Introduction The tumor microenvironment (TME) is a complex and dynamic ecosystem composed of cancer cells, stromal elements, immune infiltrates, blood vessels, and extracellular matrix components ( This oxygen deficiency activates a range of cellular adaptive mechanisms, orchestrated primarily through hypoxia-inducible factors (HIFs), particularly HIF-1 and HIF-2 ( Figure 1 ) ( Figure 2 ) ( Figure 1 Figure 2 Importantly, hypoxia-induced metabolic reprogramming not only promotes cancer cell survival but also actively contributes to immune evasion, therapeutic resistance, and a more aggressive phenotype ( Recent advances in multi-omics, single-cell analysis, and imaging technologies have deepened our understanding of the hypoxic tumor landscape and revealed novel metabolic vulnerabilities ( This review provides a comprehensive overview of the hypoxic microenvironment in cancer, with a particular focus on its role in metabolic reprogramming