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

Huo, J.; Lin, H.; Li, Y.; Tripathi, S.; Chojak, R.; Silvers, C.; Peng, Y.; Boland, L.; Zhang, J.; McCortney, K.; Perera, R. M.; Najem, H.; Billingham, L. K.; Chia, T.-Y.; Chen, X.; Wang, H.; Sun, J.; Siringan, M. J.; Jing, L.; Musabji, A.; Congivaram, H.; Wang, S.; Lopez-Rosas, A.; Kumthekar, P.; Jamshidi, P.; Ahmed, A. U.; Lee-Chang, C.; Chandler, J. P.; Youngblood, M. W.; Sonabend, A.; Tate, M. C.; Shah, H.; Thorp, E. B.; Lesniak, M. S.; Heimberger, A. B.; Miska, J.; Zhang, P.

doi:10.64898/2026.08.03.741800

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bioRxiv · 10.64898/2026.08.03.741800

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

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Abstract

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.

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Huo, J., Lin, H., Li, Y., Tripathi, S., Chojak, R., Silvers, C., Peng, Y., Boland, L., Zhang, J., McCortney, K., Perera, R. M., Najem, H., Billingham, L. K., Chia, T.-Y., Chen, X., Wang, H., Sun, J., Siringan, M. J., Jing, L., Musabji, A., Congivaram, H., Wang, S., Lopez-Rosas, A., Kumthekar, P., Jamshidi, P., Ahmed, A. U., Lee-Chang, C., Chandler, J. P., Youngblood, M. W., Sonabend, A., Tate, M. C., Shah, H., Thorp, E. B., Lesniak, M. S., Heimberger, A. B., Miska, J., Zhang, P.. 2026-08-07. Myeloid-targeted RNA nanotherapeutics rewire cholesterol metabolism to unleash anti-tumor immunity in glioblastoma. https://doi.org/10.64898/2026.08.03.741800

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