肿瘤细胞治疗研究
英文原题：Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
我们的发现共同表明，NK 细胞介导的早期免疫监视促进肝癌演进，并提示免疫代谢治疗可作为晚期肝癌的潜在策略。
肿瘤演化使肝癌细胞获得生存优势，并逃避治疗诱导的细胞死亡。然而，NK细胞在肝癌演化中的作用尚不明确。本研究建立免疫人源化的时空肝癌模型，结合单细胞、空间转录组及CRISPR/Cas9筛选分析，探究这一过程。我们发现，早期NK细胞介导的免疫监视会促进肿瘤细胞状态转变，并损害后续适应性免疫应答。从机制上看，NK细胞诱导脂质代谢重编程，尤其促进胆固醇积累，并增强肿瘤干性，二者均推动肝癌演化。此外，联合抗LAG-3治疗与肝X受体激活可抑制肿瘤演化，并改善晚期肝癌免疫检查点阻断的疗效和持久性。综上，本研究发现NK细胞介导的早期免疫监视促进肝癌演化，并提示免疫代谢疗法可能成为治疗晚期肝癌的策略。
Tumor evolution enables liver cancer cells to acquire survival advantages and evade therapy-induced cell death. However, the role of natural killer (NK) cells in liver cancer evolution remains unclear. Here, we establish immune-humanized spatiotemporal liver cancer models and integrate single-cell, spatial transcriptomic, and CRISPR/Cas9 screening analyses to investigate this process. We demonstrate that early NK cell-mediated immunosurveillance promotes tumor cell state transition and impairs subsequent adaptive immune responses. Mechanistically, NK cells induce lipid metabolic reprogramming, particularly cholesterol accumulation, and enhance tumor stemness, both of which promote liver cancer evolution. Furthermore, combined anti-LAG-3 treatment and liver X receptor activation suppress tumor evolution and improve the efficacy and durability of immune checkpoint blockade in advanced liver cancer. Collectively, our findings identify that NK cell-mediated early immunosurveillance promotes liver cancer evolution and suggest immunometabolic therapy as a potential strategy for advanced liver cancer.
MEMBER ACCOUNT
登录成功会直接打开下一页。
