Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages
- 1TU Dresden, Center for Regenerative Therapies Dresden (CRTD), 01307 Dresden, Germany
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.
Related
- Butyrate reverts Chlamydia pneumoniae -induced transcriptional suppression of macrophage polarization markers and promotes chlamydial clearance in macrophages
- P2Y6 signaling selectively regulates TLR3-induced chemokine release in murine bone marrow-derived macrophages, with opposing effects on CCL2 and CXCL1
- TGFB1-Engineered Induced Mesenchymal Stromal Cells Exhibit High Immunomodulatory Potency and Durably Reprogram Synovial Macrophages in Osteoarthritis
- Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution in mice
- Dopamine-induced mitochondrial dysfunction activates cGAS-sTING to drive IL-6 secretion in macrophages
BibTeX
@misc{nitsche2026stemness,
title = {{Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages}},
author = {J. Nitsche and C. J.-L. Busch and J. Subburayalu and J. Favret and A. Swiersy and M. Hertrich and F. Rost and D. Ivan and J. Benjamin and M. Franco and Q. Lahmar and A. Scheede and A. Stammberger and M. Giannini and Y. Zhang and M. Schmitz and L. Englmeier and S. Subramanian and S. Sarrazin and M. H. Sieweke},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756629},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756629v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages
AU - J. Nitsche
AU - C. J.-L. Busch
AU - J. Subburayalu
AU - J. Favret
AU - A. Swiersy
AU - M. Hertrich
AU - F. Rost
AU - D. Ivan
AU - J. Benjamin
AU - M. Franco
AU - Q. Lahmar
AU - A. Scheede
AU - A. Stammberger
AU - M. Giannini
AU - Y. Zhang
AU - M. Schmitz
AU - L. Englmeier
AU - S. Subramanian
AU - S. Sarrazin
AU - M. H. Sieweke
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756629
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756629v1
AB - 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.
ER -