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. 2025 Feb;26(2):188-199.
doi: 10.1038/s41590-024-02065-8. Epub 2025 Jan 21.

Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

Meriem Belabed #  1   2   3 , Matthew D Park #  1   2   3 , Cédric M Blouin  4   5   6 , Sreekumar Balan  1   2   3 , Chang Y Moon  1   2   3 , Grace Freed  2 , Miguel Quijada-Álamo  2 , Ante Peros  1   2   3 , Raphaël Mattiuz  1   2   3 , Amanda M Reid  1   2   3 , Nader Yatim  1   2   3 , Jesse Boumelha  1   2   3 , Camillia S Azimi  1   2   3 , Nelson M LaMarche  1   2   3 , Leanna Troncoso  1   2   3 , Angelo Amabile  1   2   3 , Jessica Le Berichel  1   2   3 , Steven T Chen  1   2   3 , C Matthias Wilk  1   2   3 , Brian D Brown  1   2   3 , Kristen J Radford  7 , Sourav Ghosh  8 , Carla V Rothlin  9 , Laurent Yvan-Charvet  10 , Thomas U Marron  1   2   3   11   12 , Daniel J Puleston  1   2   3 , Elvin Wagenblast  2 , Nina Bhardwaj  1   2   3 , Christophe Lamaze  4   5   6 , Miriam Merad  13   14   15
Affiliations

Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer

Meriem Belabed et al. Nat Immunol. 2025 Feb.

Abstract

Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann-Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs.

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Conflict of interest statement

Competing interests: M.M. serves on the scientific advisory board of and holds stock from Compugen, Dynavax, Innate Pharma, Morphic Therapeutics, Asher Bio, Dren Bio, Nirogy, Genenta, OncoResponse and Owkin. M.M. serves on the ad hoc scientific advisory board of DBV and Genentech and on the foundation advisory board of Breakthrough Cancer. M.M. receives funding for contracted research from Genentech, Regeneron and Boehringer Ingelheim. M.M. is listed as an inventor on a patent application (16/092576) submitted by the Icahn School of Medicine at Mount Sinai that covers the use of multiplex immunohistochemistry to characterize tumors and treatment responses. The technology is filed through the Icahn School of Medicine at Mount Sinai and is currently unlicensed. This technology was used to evaluate tissue in this study, and the results could impact the value of this technology. T.U.M. has served on advisory and/or data safety monitoring boards for Rockefeller University, Regeneron Pharmaceuticals, AbbVie, Bristol Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, Glenmark, Simcere, Surface, G1 Therapeutics, NGM Bio, DBV Technologies, Arcus and Astellas and has research grants from Regeneron, Bristol Myers Squibb, Merck and Boehringer Ingelheim. The remaining authors declare no competing interests.

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