Zhang Weihan, Yuan Shijun, Zhang Zipeng, Fu Shunli, Liu Shujun, Liu Jinhu, Ma Qingping, Xia Zhenxing, Gu Panpan, Gao Shuying, Zhang Zhiyue, Zhang Xinke, Liu Yongjun, Zhang Na
Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, China.
Biomaterials. 2025 May;316:123034. doi: 10.1016/j.biomaterials.2024.123034. Epub 2024 Dec 18.
Tumor cells transmit various immunosuppressive signals and induce a dysfunctional state in T cells, which essentially leads to immune escape and tumor progression. However, developing effective strategies to counteract the domestication of T cells by tumor cells remains a challenge. Here, we prepared pH-responsive lipid nanoparticles (NL/PLDs) co-loaded with PCSK9 shRNA, lonidamine (LND), and low-dose doxorubicin (DOX). NL/PLDs can awaken domesticated T cells function by sending pro-activation, pro-recognition, and pro-killing signals by increasing tumor immunogenicity, increasing the expression of major histocompatibility complex I (MHC-I) on tumor cells, and alleviating the suppression effect of tumor-secreted lactic acid (LA) on the T cell effector function, respectively. In melanoma-bearing mice, NL/PLDs effectively relieved tumor immunosuppressive microenvironment (TIME) and enhanced the antitumor immunity mediated by CD8 T cells. Furthermore, when combined with aPD-1, NL/PLDs demonstrated strong antitumor effects and increased immunotherapeutic efficacy. This regulatory strategy provides new insights for enhancing immunotherapy by regulating tumor immunosuppressive signals and shows significant potential for clinical tumor treatment.
肿瘤细胞传递各种免疫抑制信号并诱导T细胞进入功能失调状态，这实质上导致了免疫逃逸和肿瘤进展。然而，制定有效的策略来对抗肿瘤细胞对T细胞的驯化仍然是一项挑战。在此，我们制备了共负载PCSK9短发夹RNA、氯尼达明（LND）和低剂量阿霉素（DOX）的pH响应性脂质纳米颗粒（NL/PLDs）。NL/PLDs可以通过增加肿瘤免疫原性、增加肿瘤细胞上主要组织相容性复合体I（MHC-I）的表达以及分别减轻肿瘤分泌的乳酸（LA）对T细胞效应功能的抑制作用，发送促激活、促识别和促杀伤信号，从而唤醒驯化的T细胞功能。在荷黑素瘤小鼠中，NL/PLDs有效缓解了肿瘤免疫抑制微环境（TIME）并增强了CD8 T细胞介导的抗肿瘤免疫力。此外，当与αPD-1联合使用时，NL/PLDs表现出强大的抗肿瘤作用并提高了免疫治疗效果。这种调节策略为通过调节肿瘤免疫抑制信号增强免疫治疗提供了新的见解，并显示出在临床肿瘤治疗中的巨大潜力。
