Bsld-03 a Pan-cancer Atlas of Leptomeningeal Disease Reveals Branched Chain Keto Acids Drive Immunosuppression and Neurodegeneration
Year: 2026
Type: article
Abstract: Leptomeningeal disease (LMD) is one of the most devastating complications of advanced cancer, resulting in severe neurological deterioration and poor survival outcomes. Despite this, very little is known about the mechanisms responsible for the exceedingly poor prognosis and severely impaired neurological function of these patients. Here, we report that toxic branched-chain keto acids (BCKAs) accumulate in the cerebrospinal fluid of LMD patients and drive both immunosuppression and neurodegeneration, presenting a novel therapeutic target. Using single-cell transcriptomics and multi-omics profiling of patient specimens, we created a comprehensive LMD atlas that revealed two hallmarks of LMD: an immunosuppressive cellular microenvironment and an environment promoting neurodegeneration. Mechanistically, there is a profound BCKA-mediated disruption of both T cell function and neuronal integrity. BCKA exposure inhibits T cell viability, proliferation, energy metabolism, and effector cytokine release. Strikingly, BCKA-reducing therapy using sodium phenylbutyrate improves survival and neurological outcomes in preclinical models while enhancing the efficacy of CAR-T cell therapy in lymphoma LMD and immunecheckpoint inhibitors in melanoma LMD. Thus, BCKA accumulation is a central mediator of LMD progression and treatment resistance and provides an actionable therapeutic opportunity through drug repurposing. Importantly, our pan-cancer atlas of human LMD delivers a framework for understanding disease mechanisms and developing novel therapeutic strategies for this urgent unmet clinical need.
Source: Neuro-Oncology Advances
Authors: Mariam Khaled, Ethan Vallebuona, Yuan Ren, Taryn Rauff, Debora Endo Colodete, Lexi Grisham, Vincent Law, Mohammad Baraa Boozo, Ronak Kundalia, Jillian Baader, Hasan Alhaddad, Zhihua Chen, Gerald Wallace, Brittany Evernden, Oscar Ospina, MacLean Hall, Min Liu, Lancia Darville, Victoria Izumi, Ann Chen, Shari Pilon-Thomas, Paul Stewart, John Koomen, Salvatore Corallo, Michael Jain, Sheri Holmen, Ana Da Silva Gomes, Timothy Robinson, Fredrick Locke, Peter Forsyth, Inna Smalley
Institutions: Moffitt Cancer Center, Huntsman Cancer Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,615
OpenAlex ID: W7201872222