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Page 2 of 19 Lin et al. Cancer Drug Resist. 2026;9:14

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.

INTRODUCTION
Cancer immunotherapy has become an integral component of modern oncology. Immune checkpoint
inhibitors (ICIs) have demonstrated substantial clinical benefits by reinvigorating antitumor T-cell
responses, enabling durable tumor regression and long-term survival in a subset of patients across multiple
malignancies [1-3] . Despite these advances, important limitations continue to hinder the broader and more
consistent success of immunotherapy. Only a minority of patients derive sustained benefit, while many
exhibit primary resistance or develop acquired resistance after an initial response [4,5] . Overall,
immunotherapy represents a highly effective yet still constrained strategy for cancer treatment.

Among immune checkpoint pathways, the programmed cell death protein 1 (PD-1) and programmed
death-ligand 1 (PD-L1) axis is one of the most extensively validated therapeutic targets and has become a
cornerstone of ICI therapy. In this pathway, PD-1 expressed on activated T cells binds to PD-L1 on tumor
cells and other components of the tumor microenvironment (TME), thereby attenuating T-cell activation
and facilitating immune evasion. Although PD-1/PD-L1 blockade can restore antitumor immunity in some
patients, therapeutic resistance remains common . Notably, primary (intrinsic) resistance refers to a lack of
[6]
clinical response at the beginning of PD-1/PD-L1 inhibition.

To address these limitations, nanomaterial-based platforms offer a promising avenue. Targeted nano-drug
delivery systems can enhance tumor accumulation of immunotherapeutic agents, enable controlled or
stimuli-responsive release, and facilitate co-delivery of small molecules and nucleic acids [e.g., small
interfering RNA (siRNA)] to modulate resistance-associated pathways . Accordingly, this review focuses
[7,8]
on nanomaterial-based strategies for overcoming primary resistance to PD-1/PD-L1 blockade. It highlights
mechanistically guided approaches, including signaling pathway modulation, checkpoint gene silencing,
localized PD-1/PD-L1 interception, and TME reprogramming, all of which may help broaden and prolong
the clinical benefits of checkpoint immunotherapy.

FUNCTION OF THE PD-1/PD-L1 PATHWAY
PD-1
PD-1 (CD279) is an inhibitory receptor of the CD28/cytotoxic T-lymphocyte–associated protein 4 (CTLA-4)
family that was initially identified as a gene upregulated during programmed cell death . PD-1 is widely
[9]
expressed on activated T cells and is also inducible on B cells, monocytes, macrophages, and other immune
subsets [10] . In cancer, PD-1 functions as a key immune checkpoint that contributes to T-cell
dysfunction/exhaustion, and its upregulation on tumor-reactive T cells is associated with reduced antitumor
effector function.

PD-L1
PD-L1 (B7-H1, CD274) is the first ligand of PD-1 . It is mainly distributed in resting lymphocytes,
[11]
antigen-presenting cells (APCs), and some types of tumor cells [12,13] . In cancer, PD-L1 expression is used as a
biomarker for PD-1/PD-L1 blockade and can mediate immune escape by suppressing T-cell activity at the
tumor-immune interface .
[13]

The pathway of PD-1 and PD-L1
The interaction between PD-1 and PD-L1 plays a fundamental role in regulating T-cell recognition of tumor
cells and contributes to immune evasion through distinct signaling pathways . This axis is central to the
[14]
interplay between the host immune defense system and tumor cells. The binding of PD-1 to PD-L1
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