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Lin et al. Cancer Drug Resist. 2026;9:14 Page 7 of 19

Mechanisms of nanomaterial-based strategies
Signaling pathway
Signaling pathways play a pivotal role in the tumor intrinsic factors of primary resistance to PD-1/PD-L1
blockade. In particular, oncogenic pathways like PI3K/AKT and Wnt/β-catenin induce immune evasion,
while loss of IFN-γ signaling impairs the efficacy of the PD-1/PD-L1 blockade. Thus, focusing on the
treatments for PI3K/AKT, Wnt/β-catenin, and IFN-γ pathway will be one of the key mechanisms to
overcome the primary immune resistance of PD-1/PD-L1 therapy.

For the IFN-γ pathway, Kateh Shamshiri et al. built a non-polyethylene glycolized (HSPC/DSPG/Chol,
LIP-F1) liposome and a polyethylene glycolized (HSPC/DSPG/Chol/mPEG2000-DSPE, LIP-F2) liposome
encapsulating with IFN-γ. This combination of liposomes and IFN-γ can modulate M2 macrophage and also
upregulate the level of IFN-γ in immune cells, which provides an intense anti-tumor immune response .
[56]
Liposome is a type of nanomaterial or nanocarrier that has been discovered by Bangham and colleagues in
1965 . As people gradually improve the understanding of liposome, liposome-derived technologies are now
[57]
recognized as one of the cornerstones of bionanotechnology . Similar strategies have also been reported by
[58]
Liu et al., who developed a nebulized liposomal nanoparticle (NP) loaded with cyclic dinucleotide (CDN)
(AeroNP-CDN) for delivery to deep lung tumors . In addition to nanomaterials like liposomes, other NPs
[59]
are also essential. Sun et al. presented supramolecular NPs called HCJSP to promote the immune response
and suppress the PD-L1 expression triggered by IFN-γ signaling .
[60]

Besides IFN-γ signaling, PI3K/AKT and Wnt/β-catenin are also crucial. Zhang et al. demonstrated that an
internalizing RGD (iRGD) peptide-modified lipid nanoparticle (LNP). They used it to encapsulate PI3K
inhibitor to block the PI3K/AKT signaling pathway, which inhibits tumor-mediated immunosuppression .
[61]
In addition to directly blocking the PI3K/AKT signaling pathway, Lin et al. developed a PTEN messenger
RNA (mRNA) NP, called mPTEN@NPs, to effectively induce the PTEN expression by the targeted
delivering of mRNA to tumor sites, thus restoring the function of lost or mutated PTEN protein . The
[62]
results are shown in Figure 3 which suggests that mPTEN@NPs, by restoring PTEN, successfully
[62]
counteracted the immune resistance caused by PTEN loss. mPTEN@NPs can promote tumor cell apoptosis
and inhibit tumor growth [Figure 3B], while also demonstrating the ability to reverse the
immunosuppressive TME by reducing the proportions of Tregs [Figure 3C] and monocytic myeloid-derived
suppressor cells (Mo-MDSCs) [Figure 3D]. The enhanced immunofluorescence signal of hemagglutinin
(HA)-tagged PTEN (HA-PTEN) observed in the mPTEN@NPs-treated group [Figure 3E] indicates that
mPTEN@NPs effectively delivered PTEN mRNA to the tumor site, achieving PTEN restoration in vivo.
Increasing the expression of PTEN is an effective way to counteract the PI3K/AKT pathway and the tumor
immunosuppression. Compared with IFN-γ-related nanotechnologies, relatively few nanomaterial-based
strategies targeting the PI3K/AKT and Wnt/β-catenin pathways have been reported for overcoming primary
resistance to PD-1/PD-L1 blockade. These might be the possible fields that deserve attention in the future.

Checkpoint gene silencing
Rather than directly modulating signaling pathways, some strategies use siRNA to knock down checkpoint
genes. siRNA consists of short double-stranded RNA molecules that can be designed to knock down specific
genes . Thus, siRNA becomes a potential approach to suppress the expression of PD-L1 proteins in cancer
[63]
cells. Naked siRNA is rapidly degraded and exhibits poor membrane permeability because of its relatively
large molecular size and negative charge. Consequently, nanotechnology can be used in combination with
siRNA to improve its therapeutic performance. This is illustrated by the study conducted by Jung et al., in
which PD-L1-targeting siRNA NPs, denoted as siPD-L1@PLGA [poly(lactic-co-glycolic acid)], were used for
the treatment of pancreatic cancer . Jung et al. showed that siPD-L1@PLGA effectively silenced PD-L1 in
[64]
pancreatic cancer cells. Confocal imaging and flow cytometry confirmed efficient NP uptake in Blue #96 cells

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