Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy.

癌细胞由于其旺盛的增殖和肿瘤脉管系统不足而经常经历营养限制的条件，这导致代谢适应以维持增殖。大多数癌细胞会迅速消耗葡萄糖，而葡萄糖在营养稀缺的肿瘤微环境中会严重减少。在基于 CRISPR 的遗传筛选中，我们发现肿瘤相关葡萄糖浓度（低葡萄糖）保护癌细胞免受从头嘧啶生物合成的抑制，这是化疗经常靶向的途径。我们确定了两种机制来解释这一结果，这在癌症类型中被广泛观察到。首先，低葡萄糖限制了尿苷-5-二磷酸-葡萄糖的合成，保留了嘧啶核苷酸的可用性，从而延长了复制叉停滞的时间。其次，低葡萄糖通过抑制 BAK 激活和随后的细胞色素 c 释放（激活 caspase-9 依赖性线粒体凋亡的关键事件）直接调节复制叉停滞下游的细胞凋亡。这些结果表明，在肿瘤中经常观察到的低葡萄糖水平可能会限制特定化疗药物的疗效，这凸显了考虑肿瘤营养环境对癌症治疗影响的重要性。