CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Jiaojiao Xu, Zhe Li, Qinli Tong, Sihang Zhang, Jianchen Fang, Aihua Wu, Guoguang Wei, Chen Zhang, Sheng Yu, Binbin Zheng, Hongzheng Lin, Xueling Liao, Zeyu Xiao () and Wei Lu ()
Additional contact information
Jiaojiao Xu: Fudan University
Zhe Li: Fudan University
Qinli Tong: Fudan University
Sihang Zhang: Fudan University
Jianchen Fang: Shanghai Jiao Tong University School of Medicine
Aihua Wu: Fudan University
Guoguang Wei: Fudan University
Chen Zhang: Fudan University
Sheng Yu: Fudan University
Binbin Zheng: Fudan University
Hongzheng Lin: Fudan University
Xueling Liao: Fudan University
Zeyu Xiao: Shanghai Jiao Tong University School of Medicine
Wei Lu: Fudan University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.

Date: 2025
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DOI: 10.1038/s41467-025-55876-0

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