Year: 2026
Type: preprint
Abstract: Macrophages hold great promise for antitumour therapies 1–4 , particularly owing to their ability to infiltrate solid tumours 5 . Yet therapeutic success has been limited 6,7 , because macrophages exhibit rapid exhaustion of antitumorigenic activity in the tumour 5,8,9 . Here, we induced a stem-like self-renewal programme in human induced pluripotent stem cell (iPSC)-derived macrophages by deleting the self-renewal restricting transcription factors MAFB and MAF (MAF-DKO). Human MAF-DKO macrophages showed activated stem cell signatures, increased clonogenicity and proliferative potential. Increased self-renewal capacity was accompanied by enhanced mitochondrial fitness and invigorated energy metabolism. Importantly, these stemness features prevented exhaustion, cellular aging-associated parameters and loss of energy efficiency that are typically associated with proinflammatory macrophage activation. In addition, activated MAF-DKO macrophages showed a broad loss of IFNγ-triggered immunosuppressive pathways 10,11 , induced a super-activated state with robust cytotoxic activity and resisted exhaustion upon tumour cell exposure. Consequently, activated MAF-DKO macrophages showed intratumoral persistence with a stable antitumoral phenotype in vivo, conferred robust reduction of tumour burden and extended survival of tumourbearing mice. Together, this demonstrates that the induction of stemness in human macrophages can overcome critical roadblocks of antitumour therapy by conferring resistance to activation-triggered exhaustion of antitumour activity in the TME.
Authors: Jessica Nitsche, Clara Jana-Lui Busch, Julien Subburayalu, Jeremy Favret, Anka Swiersy, Marie Hertrich, Fabian Rost, Daniela Ivan, Jiffin Benjamin, Mauro Franco, Qods Lahmar, Annemarie Scheede, Antonia Stammberger, Mariette Giannini, Yujun Zhang, Marc Schmitz, Ludwig Englmeier, Sethuraman Subramanian, Sandrine Sarrazin, Michael H. Sieweke
Institutions: Center for Regenerative Therapies Dresden, Technische Universität Dresden, German Cancer Research Center, University Hospital Carl Gustav Carus, German Cancer Consortium (DKTK) Dresden, DRESDEN-concept Genome Center, Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Centre d’Immunologie de Marseille-Luminy, Helmholtz-Zentrum Dresden-Rossendorf, Nationales Centrum für Tumorerkrankungen Dresden
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Technische Universität Dresden, Else Kröner-Fresenius-Stiftung, Zentrum für Regenerative Therapien Dresden, Berlin Institute of Health, HORIZON EUROPE Framework Programme, HORIZON EUROPE European Innovation Council
Awards: SaxoCell: Universelle KI-geführte Designer-CAR-T-Zell-Therapie gegen Tumor-, Entzündungs- und Autoimmunerkrankungen (UniK-T) - B, G5373097964, ERA-NET Transcan - RISEBrain - Charakterisierung des immunsuppressiven Tumormikromilieus von Hirnmetastasen und dessen therapeutischer Modulation - Standort: Technische Universität Dresden, G7193030452, Innovative macrophage therapies to transform treatment paradigm of solid tumors, SaxoCell: Massenproduktion universeller Makrophagen (SaxoCell-xMac)
OpenAlex ID: W7221634762