Minor Allegra C, Couser Evan, Eichner Lillian J
Department of Biochemistry and Molecular Genetics, Northwestern University, 303 E Superior Street, Chicago, IL, USA.
Department of Biochemistry and Molecular Genetics, Northwestern University, 303 E Superior Street, Chicago, IL, USA.
Trends Pharmacol Sci. 2025 Aug;46(8):722-737. doi: 10.1016/j.tips.2025.06.008. Epub 2025 Jul 22.
Despite the development of new classes of therapeutics in oncology, patients with tumors harboring mutations in the tumor suppressor gene STK11/LKB1 continue to exhibit poor clinical response and therapeutic resistance. Recent advances in the understanding of LKB1-mutant tumor biology have illuminated how metabolism and the tumor microenvironment (TME) function as effectors of the aggressive nature of this tumor type. New findings have revealed how metabolic reprogramming, a hallmark of LKB1-mutant tumor biology, can be exploited as a potential targetable liability in these tumors. Characterization of the distinctly immunosuppressive LKB1-mutant TME has motivated multiple discoveries of new approaches for rewiring the microenvironment to overcome immunotherapy resistance. Indeed, overcoming therapeutic resistance in LKB1-deficient tumors continues to be a major research focus, and some preclinical studies have advanced to clinical trials. In this review, we critically analyze these findings and discuss therapies in development that aim to leverage this new understanding for clinical benefit.
尽管肿瘤学领域已开发出新型治疗药物，但携带肿瘤抑制基因STK11/LKB1突变的肿瘤患者仍表现出较差的临床反应和治疗抗性。对LKB1突变肿瘤生物学认识的最新进展，揭示了代谢和肿瘤微环境（TME）如何作为这种肿瘤类型侵袭性的效应器发挥作用。新发现表明，代谢重编程作为LKB1突变肿瘤生物学的一个标志，如何能被用作这些肿瘤潜在的可靶向弱点。对具有明显免疫抑制作用的LKB1突变TME的表征，促使人们多次发现重新构建微环境以克服免疫治疗抗性的新方法。事实上，克服LKB1缺陷肿瘤的治疗抗性仍然是一个主要研究重点，一些临床前研究已进入临床试验阶段。在本综述中，我们批判性地分析了这些发现，并讨论了正在开发的旨在利用这一新认识实现临床获益的疗法。
