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Multichannel Immune Nanoregulators Suppress Lactic Acid Metabolism and Lactic Acid-Shaped Acidic Microenvironment to

Chao Fang1,2, Qiuxia Peng1, Xiaoying Li3

  • 1Department of Orthopedics and Central Laboratory, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, Sichuan, 610072, China.

Advanced Materials (Deerfield Beach, Fla.)
|September 26, 2025
PubMed

Insights

This study introduces a nanoregulator to combat cancer immunosuppression by neutralizing lactic acid and reprogramming macrophages. The nanoregulator effectively targets the acidic tumor microenvironment, restoring anti-tumor immunity.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Research

Background:

  • Lactic acid (LA) and the acidic tumor microenvironment (TME) are key drivers of cancer-induced immunosuppression.
  • Existing strategies fail to effectively address LA and the acidic TME.
  • This creates a need for novel therapeutic approaches to overcome cancer immune evasion.

Purpose of the Study:

  • To engineer a multichannel immune nanoregulator capable of dampening the acidic TME and repolarizing immunosuppressive macrophages.
  • To address both the symptoms and root causes of cancer immunosuppression driven by LA and non-inflammatory macrophages.
  • To enhance the anti-tumor efficacy of existing cancer therapies.

Main Methods:

  • Fabrication of a nanoregulator using fluorocarbon chains (FC)-modified mesoporous silica (FM) as nanoreactors.
  • In situ synthesis of CaO2 and loading of R848 within the nanoreactors, followed by liposome coating and anti-CD105 modification.
  • Ultrasound-triggered oxygen release and CaO2 reactions to neutralize acidity and inhibit LA production.
  • Utilizing anti-CD105 for active targeting and accumulation within the tumor.

Main Results:

  • The nanoregulator successfully depleted existing H+ and inhibited glycolysis-derived LA production, effectively cutting off the acidic TME.
  • Repolarization of non-inflammatory M2 macrophages was achieved, mitigating a key mechanism of cancer immunosuppression.
  • Enhanced anti-tumor efficacy was observed, attributed to the nanoregulator's ability to promote cytotoxic T lymphocyte and PD1+ T cell activity.
  • Intratumoral H2O2 accumulation and anti-tumor effects were promoted, particularly after targeted delivery.

Conclusions:

  • The developed multichannel immune nanoregulator offers a novel strategy to uproot lactic acid and macrophage-induced cancer immunosuppression.
  • This approach effectively targets the acidic TME and reprograms the tumor microenvironment to restore anti-tumor immunity.
  • The findings present a promising solution for overcoming immune evasion in cancer treatment.
Keywords:
acidic tumor microenvironment attenuationanaerobic glycolysis regulationlactic acid‐associated cancer immunosuppression uprootingmultichannel immune nanoregulatorsnon‐inflammatory macrophages

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