实体瘤中癌细胞群的扩张产生了一个恶劣的环境，其特征是动态变化的酸中毒、缺氧和营养缺乏水平。由于酸中毒会抑制糖酵解代谢，缺氧会抑制氧化磷酸化，因此在这些环境中生存和生长的癌细胞必须重新连接其代谢并发展出高度的代谢可塑性，以满足其能量和生物合成的需求。癌细胞经常上调途径，从而能够摄取和利用来自死亡或补充的基质细胞的脂质和其他营养物质，特别是脂质摄取在酸性微环境中强烈增强。由此产生的脂质积累以及对β-氧化和线粒体代谢的依赖增加，增加了对氧化应激、脂毒性和铁死亡的敏感性，进而推动可能减轻此类风险的变化。因此，空间和时间上异质的肿瘤微环境选择了具有侵袭性、代谢灵活且有弹性的癌细胞，这些细胞能够利用其局部条件并寻找更有利的环境。这种表型依赖于代谢、酸中毒和致癌突变之间的相互作用，驱动代谢信号通路，例如过氧化物酶体增殖物激活受体（PPAR）。了解这些细胞的特殊脆弱性可能会发现最具侵袭性的癌细胞的新治疗能力。

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.