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

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.