Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment^1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant^3,4,5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP–AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8⁺ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

癌细胞重新连接新陈代谢，以有利于产生支持肿瘤生长和重塑肿瘤微环境的专门代谢物^1,2 。赖氨酸作为生物合成分子、能源和抗氧化剂^3,4,5 ，但对其在癌症中的病理作用知之甚少。在这里，我们发现胶质母细胞瘤干细胞（GSC）通过上调赖氨酸转运蛋白SLC7A2和巴豆酰辅酶A（巴豆酰辅酶A）生成酶戊二酰辅酶A脱氢酶（GCDH）并下调巴豆酰辅酶A水合酶烯酰基来重新编程赖氨酸分解代谢。 CoA 水合酶短链 1 (ECHS1)，导致细胞内巴豆酰辅酶 A 和组蛋白 H4 赖氨酸巴豆酰化的积累。通过基因操作或赖氨酸限制减少组蛋白赖氨酸巴豆酰化会损害肿瘤生长。在细胞核中，GCDH 与巴豆酰转移酶 CBP 相互作用，促进组蛋白赖氨酸巴豆酰化。组蛋白赖氨酸巴豆酰化的缺失会通过增强的 H3K27ac 促进免疫原性胞质双链 RNA (dsRNA) 和 dsDNA 的生成，从而刺激 RNA 传感器 MDA5 和 DNA 传感器环 GMP-AMP 合酶 (cGAS) 增强 I 型干扰素信号传导，导致 GSC 受损致瘤潜力和 CD8 ⁺ T 细胞浸润升高。限制赖氨酸的饮食与 MYC 抑制或抗 PD-1 疗法协同作用，可减缓肿瘤生长。总的来说，GSC 通过摄取和降解赖氨酸来分流巴豆酰辅酶 A 的产生，重塑染色质景观，以避免干扰素诱导的对 GSC 维持的内在影响和对免疫反应的外在影响。