Smart Nanoparticles Convert 'Cold' Tumors to 'Hot' in Immunotherapy Breakthrough
Scientists develop tumor microenvironment-responsive polymeric nanoparticles that precisely deliver immunotherapy, turning immunologically 'cold' tumors 'hot' and expanding treatment efficacy to more cancer patients.
Researchers at Southwest Jiaotong University in Chengdu, China, have published a comprehensive review in Cancer Biology & Medicine detailing the development of smart polymeric nanoparticles that respond to specific signals within the tumor microenvironment (TME) to deliver immunotherapy precisely where needed. This approach addresses a major limitation of current cancer immunotherapies, which often fail against so-called 'cold' tumors that lack immune cell infiltration, leaving many patients without effective treatment options.
The review, available online at https://doi.org/10.20892/j.issn.2095-3941.2025.0517, summarizes recent advances in TME-responsive polymeric nanoparticles that exploit unique features of tumors—such as acidic pH, elevated enzymes, reactive oxygen species (ROS), glutathione (GSH), hypoxia, and adenosine triphosphate (ATP) overexpression—to trigger controlled drug release specifically at tumor sites. By responding to these endogenous stimuli, the nanocarriers enhance antitumor immune responses while reducing systemic toxicity, a key hurdle in traditional immunotherapy that often causes severe immune-related adverse events.
The authors explain that the tumor microenvironment, once seen as a barrier, is now an opportunity. 'By designing nanoparticles that sense low pH, excess enzymes, or oxidative stress, we can deliver immunotherapy exactly where it is needed and release it only when the conditions are right. This turns the tumor's own features against it,' they said. Multi-responsive systems, which combine two or more triggers, are particularly promising because they can adapt to the highly heterogeneous and dynamic nature of tumors. For example, ROS/pH dual-responsive nanocarriers (mPEG-b-P(MTE-co-PDA)) have been used to deliver nicosamide and synergize with oncolytic viruses to induce gasdermin E-mediated pyroptosis, remodeling the immunosuppressive microenvironment and converting 'cold' tumors into immunologically 'hot' ones.
The implications of this technology are significant for patients with solid tumors that do not respond to existing immunotherapies, including melanoma, triple-negative breast cancer, glioblastoma, and colorectal cancer. By precisely controlling drug release within the TME, these smart nanoparticles could reduce severe immune-related adverse events such as cytokine release syndrome and tissue damage, making immunotherapy safer for broader patient populations. Beyond cancer, the design principles may extend to other diseases characterized by abnormal microenvironments, such as chronic inflammation and autoimmune disorders.
The research team emphasizes that future clinical translation will require scalable manufacturing, rigorous safety evaluation, and combination strategies with existing immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR)-T therapies. The study was supported by the National Natural Science Foundation of China and the Sichuan Science and Technology Program, among others.