Scientists have engineered smart polymeric nanoparticles that respond to unique signals within the tumor microenvironment, enabling precise delivery of immunotherapy to solid tumors that previously resisted treatment. The approach, detailed in a comprehensive review published in Cancer Biology & Medicine (DOI: 10.20892/j.issn.2095-3941.2025.0517), overcomes a major hurdle in cancer therapy: the inability of current immunotherapies to work against so-called 'cold' tumors that lack immune cell infiltration.
Cancer immunotherapy has transformed treatment by harnessing the immune system to eliminate tumors, but only a small subset of patients benefit. Many solid tumors remain 'cold,' characterized by poor immune cell infiltration and resistance to immune checkpoint blockade (ICB). Traditional immunotherapies such as cytokines and checkpoint inhibitors often cause severe immune-related adverse events due to off-target toxicity, poor tumor targeting, and the immunosuppressive microenvironment that surrounds tumors. Conventional nanodrug delivery systems face further obstacles including immune clearance, drug leakage, and cellular barriers that limit delivery efficiency.
The research team from the Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University in Chengdu, China, published a comprehensive article summarizing recent advances in tumor microenvironment (TME)-responsive polymeric nanoparticles. These smart nanocarriers respond to endogenous stimuli within tumors, including acidic pH, elevated enzymes, reactive oxygen species (ROS), glutathione (GSH), hypoxia, and adenosine triphosphate (ATP) overexpression. By triggering controlled drug release specifically at tumor sites, the strategy significantly enhances antitumor immune responses while reducing systemic toxicity.
The review details multiple types of TME-responsive polymeric nanoparticles. For pH-responsive systems, researchers use acid-labile bonds such as hydrazone or imine that trigger drug release in the mildly acidic tumor environment (pH ~6.5) compared to normal tissues (pH ~7.4). Enzyme-responsive nanoparticles incorporate matrix metalloproteinase (MMP)-cleavable peptide sequences that enable deep tumor penetration. Redox-responsive designs exploit elevated ROS (50–100 nM in tumors versus 20 nM in normal tissues) and GSH levels (2–10 mM in tumor cells, 7–10 times higher than normal tissues) to activate drug release through thioether or disulfide bonds. Hypoxia-responsive systems utilize azo derivatives or nitroimidazoles as sensitive linkers.
The authors highlighted multi-responsive platforms that combine two or more triggers, such as ROS/pH dual-responsive nanocarriers (mPEG-b-P(MTE-co-PDA)) that deliver the transcription factor 3 inhibitor nicosamide and synergize with oncolytic viruses (OVs) to induce gasdermin E-mediated pyroptosis. This process remodels the immunosuppressive microenvironment and converts immunologically 'cold' tumors into 'hot' tumors, dramatically improving ICB efficacy.
'The tumor microenvironment is no longer just a barrier—it has become an opportunity,' the authors said. '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 emphasized that multi-responsive systems are particularly promising because they can adapt to the highly heterogeneous and dynamic nature of tumors.
This technology holds immediate potential for patients with solid tumors that do not respond to existing immunotherapies, including melanoma, triple-negative breast cancer, glioblastoma, and colorectal cancer. The ability to precisely control drug release within the TME 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 of stimuli-responsive nanocarriers may extend to other diseases characterized by abnormal microenvironments, including chronic inflammation and autoimmune disorders.
Future clinical translation will require scalable manufacturing, rigorous safety evaluation, and combination strategies with existing ICB and chimeric antigen receptor (CAR)-T therapies.
