文章：

脂质纳米颗粒递送合成抗原使实体瘤对car介导的细胞毒性敏感

Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens 

原文发布日期：2025-05-16 

英文摘要：

Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells. 

摘要翻译：

融合抗原受体(T)细胞免疫疗法依赖于抗原靶向肿瘤相关抗原，然而由于异质性抗原表达、患者间变异以及健康细胞的肿瘤外表达，这一技术仍存在障碍。本研究致力于合成抗原以使癌细胞易于被CAR T细胞识别并清除。与肿瘤相关抗原不同，我们设计的合成抗原与体内蛋白正交，从而避免对非肿瘤部位的靶向作用，并且具有小遗传效应，以便通过脂质纳米颗粒高效地将抗原输送至肿瘤。使用 camelid 单链抗体 (VHH) 作为合成抗原，研究表明将反 VHH 的 CAR T 细胞注射到携带表达 VHH 的雌性小鼠中，能够减少多种同源和异物癌模型中的肿瘤负担，改善生存率、诱导表位扩展、抵御再挑战的肿瘤以及缓解异质性肿瘤中的抗原逃逸。本研究为使用 CAR T 细胞治疗抗原低或无表达的肿瘤提供了支持，通过体内运输合成抗原。 

原文链接：

https://www.nature.com/articles/s43018-025-00968-5