Although cancer immunotherapy has transformed treatment by harnessing the immune system to eliminate tumors, 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). In addition, 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. Based on these challenges, there is an urgent need to develop smarter delivery systems that can navigate the tumor microenvironment and release therapeutic agents with high spatial precision.
A research team from the Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University in Chengdu, China, has published (DOI: 10.20892/j.issn.2095-3941.2025.0517)a comprehensive article on tumor microenvironment (TME)-responsive polymeric nanoparticles in Cancer Biology & Medicine. The article, available online, summarizes recent advances in smart nanocarriers that respond to endogenous stimuli within tumors, highlighting how these systems can overcome key barriers in cancer immunotherapy and transform “cold” tumors into immunologically “hot” ones.
The review details multiple types of TME-responsive polymeric nanoparticles, each designed to exploit specific abnormal features of tumors. 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. For redox-responsive designs, the elevated reactive oxygen species (ROS) (50–100 nM in tumors versus 20 nM in normal tissues) and glutathione (GSH) levels (2–10 mM in tumor cells, 7–10 times higher than normal tissues) activate drug release through thioether or disulfide bonds. Hypoxia-responsive systems utilize azo derivatives or nitroimidazoles as sensitive linkers. The review also highlights 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 improvingICBefficacy.
The authors explained that the real power of these smart materials lies in their ability to respond to the tumor's own signals. “The tumor microenvironment is no longer just a barrier—it has become an opportunity,” they 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 also emphasized that multi-responsive systems are particularly promising because they can adapt to the highly heterogeneous and dynamic nature of tumors, something single-stimulus systems often fail to achieve.
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.
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References
DOI
10.20892/j.issn.2095-3941.2025.0517
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0517
Funding information
This work was supported by the National Natural Science Foundation of China (Grant Nos. 52033007, 52495011, and 32371466), the Sichuan Science and Technology Program (Grant Nos. 2025ZNSFSC0887 and 2024NSFTD0002), and the Fundamental Research Funds for the Central Universities (Grant Nos. 2682025CX047 and 2682023ZTPY055).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).