What is the clinical evidence from this study?

Study design: Other. Population: Solid tumors (Melanoma, Triple-Negative Breast Cancer, Head and Neck Squamous Cell Carcinoma). Intervention: ACE-expressing iPSC-derived human macrophages (ACE-iMac) vs. Control iPSC-derived macrophages (iMac) or PBS. Primary outcome: Reduction in solid tumor size/volume (p=<0.0001).

What question did this study set out to answer?

This research aims to explore the use of genetically engineered iPSC-derived macrophages with increased ACE expression for cancer immunotherapy.

April 15, 2026Open Access

Bioengineered iPSC-derived human macrophages with increased angiotensin-converting enzyme (ACE) expression suppress solid tumor growth

Q: What are the key findings of this study?

ACE-expressing iPSC-derived human macrophages (ACE-iMac) significantly reduced solid tumor size by 3.4- to 7.2-fold compared to control macrophages in melanoma, breast cancer, and HNSCC xenograft models.

Q: What question did this study set out to answer?

This research aims to explore the use of genetically engineered iPSC-derived macrophages with increased ACE expression for cancer immunotherapy.

Key Result

ACE-expressing iPSC-derived human macrophages (ACE-iMac) significantly reduced solid tumor size by 3.4- to 7.2-fold compared to control macrophages in melanoma, breast cancer, and HNSCC xenograft models.

Key Points

This research aims to explore the use of genetically engineered iPSC-derived macrophages with increased ACE expression for cancer immunotherapy.
Developed human macrophages from genetically modified iPSCs with ACE regulation by doxycycline.
Tested ACE-iMac in vitro for tumor cell killing efficiency compared to iMac.
Conducted in vivo studies using tumor xenografts in melanoma, breast cancer, and HNSCC models.
Utilized a humanized BLT-NSG mouse model to evaluate immune response enhancement.
ACE-iMac showed significantly greater tumor cell killing in vitro than iMac.
In vivo studies demonstrated 3.4- to 7.2-fold reduction in tumor size with ACE-iMac treatment.
ACE-iMac treatment led to increased activation of human T cells and NK cells, enhancing anti-tumor effects.

Structured PICO

Does ACE-iMac immunotherapy reduce solid tumor growth in preclinical models?

Population

In vitro tumor cells, in vivo tumor xenografts for melanoma, breast cancer, and head and neck squamous cell carcinoma (HNSCC) in mice, and a humanized BLT-NSG mouse model with human melanoma xenografts

Intervention

Human macrophages derived from genetically engineered iPSCs (iMac) with angiotensin-converting enzyme (ACE) expression regulatable by a doxycycline (dox)-inducible promoter (ACE-iMac)

Comparator

iMac (without increased ACE expression)

Outcome

Reduction in solid tumor size/growthsurrogate

Enhancing ACE expression in human iPSC-derived macrophages significantly reduces solid tumor growth in preclinical models, suggesting a novel anti-cancer immunotherapy.

Main Result

p-value: p=<0.0001

Limitations

Limited to testing iMac therapy on subcutaneous tumors via direct intratumor injections, requiring future evaluation of intravenous administration.
Potential risk for cytokine release syndrome and autoimmune pathology due to the upregulation of pro-inflammatory cytokines like TNFα and IL-6.
Concerns regarding the tumorigenic potential of undifferentiated iPSCs in clinical translation.

Abstract

The potential of the immune system to decrease cancer progression is widely recognized and has led to the development of innovative anti-cancer immunotherapies. Here, we studied human macrophages derived from genetically engineered iPSCs (iMac) with angiotensin-converting enzyme (ACE) expression regulatable by a doxycycline (dox)-inducible promoter as a novel anti-cancer immunotherapy. Increased ACE expression in iMac (cells now termed ACE-iMac) augments polarization towards an M1 macrophage phenotype characterized by increased production of proinflammatory cytokines, reactive oxygen species, nitric oxide, and an RNA profile indicating an aggressive immune response. ACE-iMac kills tumor cells in vitro significantly better than iMac. In vivo, studies using tumor xenografts for melanoma, breast cancer, and head and neck squamous cell carcinoma (HNSCC) showed a highly significant 3.4- to 7.2-fold reduction in solid tumor size following ACE-expressing ACE-iMac immunotherapy as compared to results with iMac. To further investigate the impact of ACE on human anti-tumor responses, we developed a humanized BLT-NSG mouse model with a fully functional adaptive immune system. Here, ACE-iMac treatment significantly reduced the growth of human melanoma xenografts by enhancing the activation of human T cells and NK cells. In conclusion, enhancing ACE expression in human-derived macrophages (ACE-iMac) greatly amplifies their anti-cancer phenotype, offering a compelling new therapeutic strategy with the potential to improve clinical outcomes for cancer patients.

Bookmark

View Full Paper