Myeloid-targeted RNA nanotherapeutics rewire cholesterol metabolism to unleash anti-tumor immunity in glioblastoma

作者：Jiawei Huo, Hanchen Lin, Yinmeng Li, Shashwat Tripathi, Rafał Chojak, Caylee Silvers, Yirui Peng, Lauren Boland, Jianzhong Zhang, Kathleen McCortney, Rasangi M. Perera, Hinda Najem, Leah K. Billingham, Tzu-Yi Chia, Xiaoyang Chen, Hanxiang Wang, Jingqi Sun, Mark John Siringan, Leon Jing, Amaan Musabji, Harrshavasan Congivaram, Si Wang, Aurora Lopez‐Rosas, P. Kumthekar, Pouya Jamshidi, Atique U. Ahmed, Catalina Lee-Chang, James P. Chandler, Mark W. Youngblood, Adam Sonabend, Matthew C. Tate, Hardik Shah, Edward B. Thorp, Maciej S. Lesniak, Amy B. Heimberger, Jason Miska, Peng Zhang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.08.03.741800 · 研究领域：Immune cells in cancer、Immunotherapy and Immune Responses、Cholesterol and Lipid Metabolism

Tumor-associated myeloid cells (TAMCs) dominate the glioblastoma (GBM) microenvironment and suppress anti-tumor immunity. Here, we identify cholesterol efflux via ABCA1 as a targetable metabolic checkpoint controlling TAMC immunosuppression in GBM. Reprogramming TAMC cholesterol metabolism using TAMC-targeting lipid nanoparticle encapsulating ABCA1 siRNA (ABCA1 LNP) converts TAMCs into potent antigen-presenting cells with enhanced pro-inflammatory activity and antigen-presenting capacity, thereby inducing T cell activation, expansion, and tumor infiltration. Mechanistically, ABCA1 blockade induces cholesterol accumulation in TAMC membranes, promoting lipid raft formation and enhancing MHC-I-mediated antigen presentation. In multiple preclinical GBM models, ABCA1 LNP treatment dramatically induces T cell priming, extends animal survival, and overcomes GBM resistance to radiotherapy and immune checkpoint therapy. This efficacy was well-maintained in stem-like and recurrent GBM models, GBM patient specimens, and a renal cell carcinoma model. Altogether, our work identifies cholesterol efflux as a targetable metabolic vulnerability in TAMCs to overcome therapy resistance in myeloid-rich, immunologically cold tumors.