Adoptive macrophage therapy has emerged as a promising strategy to combat solid tumors due to the phenotypic plasticity of macrophages, the tumor-penetrating capacity and the ability to modulate the tumor microenvironment. Currently, various genetic approaches have been developed to engineer macrophages with chimeric antigen receptor (CAR-MΦ) for adoptive macrophage therapy. Although CAR-MΦ has demonstrated safety and antitumor activity in clinical trials, the overall response rate in patients remains suboptimal. The therapeutic efficacy of CAR-MΦ is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive.

Unlike CAR-MΦ, the nanoparticle-engineered macrophages (NPs-MΦ) eliminate tumor cells in a tumor antigen-agnostic manner, offering a potential and universal model for investigating the mechanisms of resistance to adoptive macrophage therapy. Using NPs-MΦ adoptive therapy in melanoma, the research groups identified a subpopulation of CD133⁺PD-L1⁺ cancer cells, and demonstrated their role in melanoma resistance to the adoptive macrophage therapy. The CD133⁺PD-L1⁺ cancer cells overexpressed immunosuppressive molecules to activate the transforming growth factor-β (TGF-β) signaling pathway in the tumor. The elevated TGF-β in the relapsed tumor induced the cancer-associated fibroblasts (CAFs) to enhance the stiffness of extracellular matrix (ECM), thus prohibiting the transferred macrophages and the infiltrated effector cells from trafficking and infiltration. Additionally, the CD133⁺PD-L1⁺ cancer cells dampened the phagocytotic capacity of the adoptive macrophages as well as the tumor cell-killing capability of the effector cells through the immunosuppressive factors, such as TGF-β, interleukin-10 (IL-10) and vascular endothelial growth factor-alpha (VEGF-α).

Based on the resistance mechanism, the research groups explored the feasibility of various combination therapies to overcome the resistance to adoptive macrophage therapy. Among these, adjuvant hyperthermia was proven to reverse the resistance of CD133⁺PD-L1⁺ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy.

This research was published online in Nature Communications entitled “CD133⁺PD-L1⁺ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma”.

Dr. Jiaojiao Xu from School of Pharmacy of Fudan University is the first author of this article. Professor Wei Lu from School of Pharmacy of Fudan University and Professor Zeyu Xiao from Shanghai Jiao Tong University School of Medicine are the co-corresponding authors of this paper. This research was supported by the grants from National Natural Science Foundation of China, National Postdoctoral Program for Innovative Talents, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality and Shanghai Municipal Health Commission.

J. Xu, Z. Li, Q. Tong, S. Zhang, J. Fang, A. Wu, G. Wei, C. Zhang, S. Yu, B. Zheng, H. Lin, X. Liao, Z. Xiao*, W. Lu*, CD133⁺PD-L1⁺ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma. Nature Communications 16 (1), 895 (2025).

Web link: https://www.nature.com/articles/s41467-025-55876-0