Frlic Tjaša, Pavlin Mojca
Institute of Biophysics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Front Immunol. 2025 Nov 19;16:1688995. doi: 10.3389/fimmu.2025.1688995. eCollection 2025.
Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized hematological cancer treatment, but its efficacy in solid tumors remains limited by the immunosuppressive and metabolically hostile tumor microenvironment (TME). CAR T cells' functional compromise, exhaustion, and poor persistence are critically linked to their suboptimal metabolic fitness. This review highlights a paradigm shift: immunometabolism and its intricate interplay with epigenetics profoundly regulate T cell fate and function, establishing their reprogramming as a cornerstone for optimizing CAR T cell efficacy in diverse malignancies. We explore the intricate relationship between T cell differentiation and metabolic states, emphasizing that modulating CAR T cell metabolism during manufacturing can drive differentiation towards less exhausted, more persistent memory phenotypes, such as stem cell central memory (T) and central memory (T) cells, which correlate with superior anti-tumor responses. Our analysis demonstrates that metabolic inhibitors offer significant potential to reprogram CAR T cells. Agents targeting glycolysis or the PI3K/Akt/mTOR pathway promote a memory-like phenotype by favoring oxidative phosphorylation (OXPHOS). Further strategies utilizing glutamine antagonists, mitochondrial modulators, or enzyme manipulation (e.g., IDH2, ACAT1) can epigenetically reprogram cells, fostering memory and exhaustion resistance. Similarly, nutrient level optimization during expansion directly sculpts CAR T cell metabolic profiles. With approaches like glucose restriction/galactose substitution, or specific amino acid modulation (e.g., L-arginine, asparagine), persistence of CAR T cells in patients can be improved. The judicious selection and engineering of cytokines (e.g., IL-7, IL-15, IL-21) during manufacturing also plays a vital role in fostering desired memory phenotypes. In conclusion, metabolic engineering, leveraging its impact on epigenetic regulation during CAR T cell manufacturing, is crucial for generating potent, persistent, and functionally resilient products. This approach holds immense promise for expanding the curative potential of CAR T cell therapy to a broader range of cancers, particularly challenging solid tumors.
嵌合抗原受体（CAR）T细胞疗法彻底改变了血液系统癌症的治疗方式，但其在实体瘤中的疗效仍受到免疫抑制和代谢恶劣的肿瘤微环境（TME）的限制。CAR T细胞的功能受损、耗竭及持久性差与其代谢适应性欠佳密切相关。本综述强调了一个范式转变：免疫代谢及其与表观遗传学的复杂相互作用深刻调节T细胞命运和功能，将其重编程确立为优化CAR T细胞在多种恶性肿瘤中疗效的基石。我们探讨了T细胞分化与代谢状态之间的复杂关系，强调在制备过程中调节CAR T细胞代谢可驱动其向耗竭程度较低、更持久的记忆表型分化，如干细胞中央记忆T细胞和中央记忆T细胞，这些表型与卓越的抗肿瘤反应相关。我们的分析表明，代谢抑制剂在重编程CAR T细胞方面具有巨大潜力。靶向糖酵解或PI3K/Akt/mTOR通路的药物通过促进氧化磷酸化（OXPHOS）来促进记忆样表型。利用谷氨酰胺拮抗剂、线粒体调节剂或酶操作（如IDH2、ACAT1）的进一步策略可在表观遗传上重编程细胞，增强记忆和抗耗竭能力。同样，在扩增过程中优化营养水平可直接塑造CAR T细胞的代谢谱。通过葡萄糖限制/半乳糖替代或特定氨基酸调节（如L-精氨酸、天冬酰胺）等方法，可提高CAR T细胞在患者体内的持久性。在制备过程中明智地选择和设计细胞因子（如IL-7、IL-15、IL-21）在促进所需记忆表型方面也起着至关重要的作用。总之，代谢工程利用其在CAR T细胞制备过程中对表观遗传调控的影响，对于生成强大、持久且功能有弹性的产品至关重要。这种方法对于将CAR T细胞疗法的治愈潜力扩展到更广泛的癌症，尤其是具有挑战性的实体瘤，具有巨大的前景。
