肿瘤细胞治疗研究
英文原题：Enforced BATF expression via clinically approved LNPs enhances adoptive T-cell therapies.
Enforced BATF expression via clinically approved LNPs enhances adoptive T-cell therapies.
嵌合抗原受体（CAR）T 细胞疗法在血液系统恶性肿瘤中高度有效，但其持久性受限于扩增不足、持续性不足和 T 细胞耗竭。
嵌合抗原受体（CAR）T细胞疗法对血液系统恶性肿瘤疗效显著，但扩增不足、持久性有限和T细胞耗竭影响其持久疗效。碱性亮氨酸拉链ATF样转录因子（BATF）可促进CD8+ T细胞效应分化，但在慢性刺激下也可能驱动耗竭。本研究采用临床批准的脂质纳米颗粒（LNP），开发一种瞬时、非病毒策略，以调节治疗性T细胞中的BATF表达。在3种美国FDA批准的可电离脂质中，基于SM-102的LNP在原代T细胞中实现最高mRNA递送效率。瞬时过表达BATF可增强体外T细胞细胞毒性，且未诱导耗竭。体内实验中，BATF mRNA转染增强了T细胞扩增、减少耗竭，并提高黑色素瘤模型中的OT-1 TCR-T细胞和急性淋巴细胞白血病模型中的CD19 CAR-T细胞抗肿瘤活性。这些发现建立了一个安全且可逆的转录因子瞬时调节平台，可优化T细胞分化和功能，从而增强过继T细胞疗法疗效并支持临床转化。
Chimeric antigen receptor (CAR) T-cell therapy is highly effective in hematologic malignancies, yet its durability is limited by insufficient expansion, persistence, and T-cell exhaustion. Basic leucine zipper ATF-like transcription factor (BATF) promotes CD8 + T-cell effector differentiation but can drive exhaustion under chronic stimulation. Here, we developed a transient, non-viral strategy to modulate BATF expression in therapeutic T cells using clinically approved lipid nanoparticles (LNPs). Among 3 Food and Drug Administration (FDA)-approved ionizable lipids, SM-102-based LNPs achieved the highest mRNA delivery efficiency in primary T cells. Transient BATF overexpression enhanced T-cell cytotoxicity in vitro without inducing exhaustion. In vivo, BATF mRNA transfection enhanced T-cell expansion, reduced exhaustion, and improved anti-tumor activity for both OT-1 TCR-T cells in melanoma and CD19 CAR-T cells in acute lymphoblastic leukemia. These findings establish a safe and reversible platform for transient transcription factor modulation to optimize T-cell differentiation and function, thereby enhancing the efficacy of adoptive T-cell therapies and supporting clinical translation.
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