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Lin et al. Cancer Drug Resist. 2026;9:14 Page 11 of 19

tumor-associated macrophages (TAMs), MDSCs, and other components of the microenvironment to
prevent the formation of an immunosuppressive TME .
[71]
The study by Chen et al. developed a combination of a nanovaccine with aPD-1, aOX40, and ibrutinib that
enhanced immune-cell infiltration and reduced immunosuppression. To achieve that, the aPD-1 can
effectively block the PD-1/PD-L1 pathway; aOX40 can stimulate immune activation and enhanced
immune-cell infiltration; and ibrutinib (a MDSCs inhibitor) can counteract MDSCs-mediated
immunosuppression. The nanovaccine delivered to the TME will downregulate the level of MDSCs and
block the PD-1/PD-L1 pathway, thus promoting the immune response and avoiding the immune resistance
of PD-1/PD-L1 . In order to mediate the immunosuppressive TME, there are other studies that developed
[72]
effective strategies like lipid-encapsulated calcium phosphate NPs loaded with gemcitabine to exhaust
MDSCs , and mesoporous silica NPs loaded with all-trans retinoic acid and doxorubicin, coated with IL-2
[73]
and subsequently modified with dipalmitoyl phosphatidylcholine cholesterol and DSPE-PEG 2000 to reduce
the MDSCs population .
[74]

In addition to MDSCs, Wang et al. designed an aPD-L1/indocyanine green (ICG)-based
TIME-sensitivenanoparticle (S-aPD-L1/ICG@NP) to activate T cells by blocking the overexpressed PD-L1
on the surface of tumor cells within the TIME. Other than blocking PD-1/PD-L1, the tumor-infiltrating
CD8 T cell ratio and secretion of IFN-γ and TNF-α are also increased thereby enhancing antitumor immune
+
response .
[75]
The summary list of representative nano-platforms are included in the Table 1.

CHALLENGES AND CLINICAL TRANSLATION CONSIDERATIONS FOR
NANOMATERIAL-ENABLED PD-1/PD-L1 IMMUNOTHERAPY
Why translation remains difficult
Nanomaterial-based approaches, such as NPs carrying checkpoint-blocking biologics, pathway inhibitors, or
nucleic acids to sensitize tumors to PD-1/PD-L1 therapy, are conceptually promising. However, recent
translational analyses have shown that several fundamental barriers continue to prevent or delay clinical
success. These barriers include limited exposure at the target tissue/cell, incomplete understanding of how
physicochemical attributes influence in vivo performance, poor reproducibility of preclinical outcomes in
clinical trials, biocompatibility concerns, and downstream bottlenecks such as industrial scale-up, good
manufacturing practice (GMP)-compliant manufacturing and regulatory navigation . In parallel,
[76]
oncology-focused delivery reviews highlight that even highly mature nucleic acid-based nanoplatforms (e.g.,
mRNA-LNPs) face interconnected physiological, technological, and manufacturing challenges before they
can reliably deliver clinical benefit, especially when positioned to complement or improve established
immunotherapies .
[77]

Delivery heterogeneity and the “EPR gap” between models and patients
A central translational challenge is that many nano-immunotherapy concepts still depend on passive tumor
accumulation through the enhanced permeability and retention (EPR) effect. A mechanistic and clinically
oriented review in Journal of Controlled Release concludes that the EPR effect is highly variable and thus
unreliable because of TME complexity, and stresses that understanding differences between animal and
human tumors is essential for translation .
[78]

Clinical inconsistency is also driven by methodological limitations. A recent study notes that, despite the
widespread use of the EPR concept, clinical outcomes remain inconsistent, in part due to limited mechanistic

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