Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages

Nitsche, J.; Busch, C. J.-L.; Subburayalu, J.; Favret, J.; Swiersy, A.; Hertrich, M.; Rost, F.; Ivan, D.; Benjamin, J.; Franco, M.; Lahmar, Q.; Scheede, A.; Stammberger, A.; Giannini, M.; Zhang, Y.; Schmitz, M.; Englmeier, L.; Subramanian, S.; Sarrazin, S.; Sieweke, M. H.

doi:10.64898/2026.10.06.756629

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bioRxiv · 10.64898/2026.10.06.756629

Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages

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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 IFN{gamma}-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 tumour-bearing 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.

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Nitsche, J., Busch, C. J.-L., Subburayalu, J., Favret, J., Swiersy, A., Hertrich, M., Rost, F., Ivan, D., Benjamin, J., Franco, M., Lahmar, Q., Scheede, A., Stammberger, A., Giannini, M., Zhang, Y., Schmitz, M., Englmeier, L., Subramanian, S., Sarrazin, S., Sieweke, M. H.. 2026-10-13. Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages. https://doi.org/10.64898/2026.10.06.756629

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