Reprogramming Hypoxic Tumor-Associated Macrophages by Nanoglycoclusters for Boosted Cancer Immunotherapy

Yong Dan Zhao, Hong Wei An, Muhetaerjiang Mamuti, Xiang Zhong Zeng, Rui Zheng, Jia Yang, Wei Zhou, Yuxin Liang, Gege Qin, Da Yong Hou, Xiaolong Liu, Hao Wang, Yuliang Zhao, Xiaohong Fang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


The tumor-associated macrophages (TAMs) in intratumoral hypoxic regions are key drivers of immune escape. Reprogramming the hypoxic TAMs to antitumor phenotype holds great therapeutic benefits but remains challenging for current drugs. Here, an in situ activated nanoglycocluster is reported to realize effective tumor penetration and potent repolarization of hypoxic TAMs. Triggered by the hypoxia-upregulated matrix metalloproteinase-2 (MMP-2), the nanoglycocluster is self-assembled from the administered mannose-containing precursor glycopeptides and presents densely-arrayed mannoses to multivalently engage with mannose receptors on M2-like TAMs for efficient phenotype switch. By virtue of the high diffusivity of precursor glycopeptides due to their low molecular mass and weak affinity with TAMs in perivascular regions, the nanoglycoclusters are capable of substantially accumulating in hypoxic areas to strongly interact with local TAMs. This enables the efficient repolarization of overall TAMs with a higher rate than the small-molecule drug R848 and CD40 antibody, and beneficial therapeutic effects in mouse tumor models especially when combining with PD-1 antibody. This on-demand activated immunoagent is endowed with tumor-penetrating properties and inspires the design of diverse intelligent nanomedicines for hypoxia-related cancer immunotherapy.

Original languageEnglish (US)
Article number2211332
JournalAdvanced Materials
Issue number24
StatePublished - Jun 15 2023


  • cancer immunotherapy
  • glycopeptides
  • hypoxia
  • nanoglycoclusters
  • tumor-associated macrophages

ASJC Scopus subject areas

  • Materials Science(all)
  • Mechanics of Materials
  • Mechanical Engineering


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