肿瘤微环境（TME）由肿瘤细胞、非肿瘤细胞、细胞外基质和信号分子组成，可促进肿瘤的发生、进展和治疗耐药。为了应对饥饿、缺氧和药物治疗，肿瘤细胞会经历各种有害的内源性应激，例如缺氧、DNA 损伤和氧化应激。在这种情况下，为了在困难的情况下生存，肿瘤细胞进化出多种保守的适应性反应，包括代谢重编程、DNA损伤检查点、同源重组、上调抗氧化途径和激活的未折叠蛋白反应。在过去的几十年中，蛋白质 O-GlcNAcylation 已成为葡萄糖代谢和肿瘤进展之间的关键因果关系。在这里，我们讨论调节上述反应的相关途径。这些途径是细胞内源性应激诱导的适应性调整。此外，我们系统地讨论了 O-GlcNAcylation 调节的应激诱导适应性反应途径 (SARP) 在 TME 重塑、肿瘤进展和治疗抵抗中的作用。我们还强调通过调节 OGT 或 OGA 活性的化合物来靶向 O-GlcNAcylation 来抑制肿瘤进展。看来，靶向 O-GlcNAcNA 酰化蛋白干预 TME 可能是改善肿瘤预后的一种新方法。版权所有 © 2024。由 Elsevier B.V. 出版。

The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.Copyright © 2024. Published by Elsevier B.V.