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Updated: May 19, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Nanomaterial-based strategies overcome PD-1 related intrinsic immune resistance
Yiyang Lin1,2, Jianliang Shen2,3
1Department of Bioengineering, Northeastern University, Boston, MA 02108, USA.
Abstract:
Immune-checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have substantially improved outcomes for patients with multiple cancer types; however, primary (intrinsic) resistance remains common and limits durable responses. Mechanistically, such resistance can arise from impaired interferon-γ signaling (including Janus kinases-signal transducer and activator of transcription dysfunction), tumor-intrinsic oncogenic pathway alterations [e.g., phosphatase and tensin homolog (PTEN) loss with downstream phosphoinositide 3-kinase/protein kinase B hyperactivation and Wnt/β-catenin-associated immune escape], and tumor-extrinsic immunosuppression mediated by PD-L1-upregulated suppressive myeloid populations such as myeloid-derived suppressor cells. These pathways converge on reduced T-cell effector function, compromised immune recognition, and reinforcement of an immunosuppressive tumor microenvironment (TME), collectively diminishing the clinical benefit of PD-1/PD-L1 blockade. In this review, we synthesize current evidence on primary (intrinsic) resistance to PD-1/PD-L1 blockade and discuss how nanomaterial-enabled interventions can be mechanistically matched to these resistance determinants. The nanotechnology-based therapeutic strategies were classified as four categories: (i) modulation of resistance-associated signaling pathways; (ii) direct blockade/interception of the PD-1/PD-L1 axis; (iii) immune-checkpoint gene silencing; and (iv) TME reprogramming.
Insights
Primary resistance to cancer immunotherapies like PD-1/PD-L1 blockade is common. Nanotechnology offers novel strategies to overcome resistance by targeting signaling pathways, immune checkpoints, and the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Immune-checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have revolutionized cancer treatment.
- However, primary resistance to these therapies limits durable clinical responses in many patients.
- Resistance mechanisms involve impaired interferon-γ signaling, oncogenic pathway alterations (e.g., PTEN loss), and tumor-extrinsic immunosuppression.
Purpose of the Study:
- To review primary resistance mechanisms to PD-1/PD-L1 blockade in cancer.
- To explore how nanotechnology-based interventions can address these resistance determinants.
- To categorize nanotechnology strategies for overcoming immunotherapy resistance.
Main Methods:
- Synthesis of current evidence on primary resistance to PD-1/PD-L1 blockade.
- Classification of nanotechnology-based therapeutic strategies into four categories.
- Discussion of mechanistic matching of interventions to resistance factors.
Main Results:
- Primary resistance to PD-1/PD-L1 blockade is multifactorial, involving intrinsic and extrinsic immunosuppressive mechanisms.
- Nanomaterial-enabled interventions offer promising strategies to overcome resistance.
- These strategies include modulating signaling pathways, direct PD-1/PD-L1 blockade, gene silencing, and tumor microenvironment reprogramming.
Conclusions:
- Understanding resistance mechanisms is crucial for developing effective cancer immunotherapies.
- Nanotechnology provides a versatile platform for designing targeted interventions against PD-1/PD-L1 blockade resistance.
- Future research should focus on mechanistically matching nanotechnologies to specific resistance profiles for improved patient outcomes.
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