Intracranial Targeting of Cholesterol Processing Reveals a Therapeutic Vulnerability that Reprograms Glioblastoma and Promotes Antitumor Immunity
Year: 2026
Type: preprint
Abstract: Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.
Authors: Maria J. Ulloa-Navas, Rachel M. Whitehead, Vanessa K. Jones, Michaelides Loizos, Mieu Brooks, Aleeshba N. Basil, Raquel Morales-Gallel, Cristina Gomez-Palmero, G. Abril Reynaga-Macias, Jesus E. Sanchez-Garavito, Brianna Tapia-Dierking, Asha A. Nair, Juan P. Navarro-Garcia de Llano, Paula Schiapparelli, Ian Dryden, Steven Rosenfeld, Victoria E. Clark, Haidong Dong, Loic Deleyrolle, Hong Qin, Vicente Herranz-Perez, Yingxue Ren, Jose M. Garcia-Verdugo, Alfredo Quinones-Hinojosa
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Award: G5873352142
OpenAlex ID: W7203771797
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