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Review | Open Access

Cancer Drug Resistance

Lin et al. Cancer Drug Resist. 2026;9:14 DOI:10.20517/cdr.2025.207

Nanomaterial-based strategies overcome PD-1
related intrinsic immune resistance

Yiyang Lin , Jianliang Shen 2,3
1,2
Keywords:
PD-1/PD-L1,
immunotherapy, immune
resistance, nanomaterials

Citation: Lin Y, Shen J.
Nanomaterial-based
strategies overcome PD-1
related intrinsic immune
resistance. Cancer Drug
Resist. 2026;9:14.
https://dx.doi.org/10.20517
/cdr.2025.207
Received: 17 Nov 2025
First Decision: 4 Feb
2026
Revised: 18 Mar 2026
Accepted: 10 Apr 2026 Abstract
Published: 21 Apr 2026
Immune-checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or
Academic Editor: programmed death-ligand 1 (PD-L1) have substantially improved outcomes for patients
Chiara Riganti with multiple cancer types; however, primary (intrinsic) resistance remains common and
Copy Editor: limits durable responses. Mechanistically, such resistance can arise from impaired
Pei-Yun Wang
Production Editor: interferon-γ signaling (including Janus kinases-signal transducer and activator of
Pei-Yun Wang 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

1 Department of Bioengineering, Northeastern University, Boston, MA 02108, USA.
2 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang, China.
3 National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou 325027,
Zhejiang, China.

Correspondence to: Prof. Jianliang Shen, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, Zhejiang,
China. E-mail: shenjl@wiucas.ac.cn

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