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Page 12 of 19 Lin et al. Cancer Drug Resist. 2026;9:14

Table 1. Summary of representative nano-platforms to overcome PD-1/PD-L1 resistance
Evidence
Setting level (in
(primary Cancer
Platform Payload Target/pathway vitro/in Endpoints
vs. vivo/phase model
acquired)
I/phase II)
↑ IFN-stimulated
genes in TAMs; ↓
Nebulized liposomal NP STING agonist STING pathway; Acquired In vivo Lung tumor IFN-γ-driven PD-L1
(AeroNP-CDN) (c-di-GMP) IFN genes model
upregulation in tumor
cells [59]
↑ DC activation; ↓
Peptide/polymeric Pancreatic tumor PD-L1
HCJSP supramolecular NP IFN-γ; PD-L1 axis Acquired In vivo
complex cancer expression; enhanced
T cell killing [60]
↓ PI3K/AKT signaling;
PI3K inhibitor 4T1 breast reduced tumor
iRGD peptide-modified lipid NP PI3K/AKT pathway Primary In vivo
(small molecule) cancer immunosuppression;
↑ T cell activity [61]
↑ PTEN expression; ↑
PTEN-null
Restores PTEN; melanoma; cell death
Polymeric NP PTEN mRNA antagonizes Primary In vivo PTEN-null (autophagy); ↑ CD8 +
PI3K/AKT T cells; cytokines; ↑
prostate
Tregs/MDSCs [62]
↓ Tumor PD-L1; ↑
PD-L1 gene Pancreatic
PLGA NP siPD-L1 (siRNA) Primary In vivo CD8 T cells; tumor
+
silencing cancer
growth inhibition [64]
↑ CD8 T cell
+
siPD-1 and siPD-L1 PD-1/PD-L1 cytotoxicity; ↑ IFN-γ,
LCN Primary In vivo breast cancer
(siRNAs) blockade TNF-α; improved
tumor control [65]
↓ Tumor PD-L1; ↑
Tumor-targeting SLN siPD-L1 (siRNA) PD-L1 silencing Primary In vivo Glioblastoma survival of
tumor-bearing mice [66]
↑ Tumor penetration;
PD-L1 gene Malignant ↑ PD-L1 knockdown;
HAase/pH-sensitive NP shPD-L1 (shRNA) Primary In vivo
silencing melanoma enhanced immune
response [67]
PD-1/PD-L1 BBB penetration; ↓
Macrophage-membrane-coated PD-1 on membrane
PLGA NP (PD-1-MM@PLGA) + RAPA blockade; mTOR Primary In vivo Glioblastoma tumor PD-L1; tumor
inhibition growth inhibition [68]
PD-1/PD-L1 ↓ Tumor PD-L1; ↑ T
PD-1/LAG-3-decorated
nanovesicle (IGU-Rh-PD-1) IGU + Rh NPs blockade; mTOR Primary In vivo Lung cancer cell activation; tumor
pathway suppression [69]
↑ Tumor-infiltrating
Dual pH-sensitive nanodrug CUR + anti-PD-1 PD-1 blockade; Primary In vivo B16F10 CD8 /CD4 ; ↑
+
+
(CUR@PPC-aPD-1) Ab NF-κB inhibition melanoma IFN-γ/TNF-α; ↓ tumor
growth; ↑ survival [70]
↓ MDSCs; block the
Combination of nanovaccine aPD-1 + aOX40 + MDSC inhibition Primary In vivo Breast cancer PD-1/PD-L1
with aPD-1, aOX40, and ibrutinib ibrutinib
pathway [72]
4T1
Gemcitabine-CaP NP Gemcitabine MDSC depletion Acquired In vivo mammary ↓ MDSCs; ↑ response
(lipid-coated) to PD-L1 blockade [73]
carcinoma
↑ Tumor-infiltrating
+
CD8 T cells; ↑
aPD-L1 antibody +
aPD-L1/ICG TIME-sensitive NP PD-L1 blockade Primary In vivo Melanoma IFN-γ/TNF-α;
ICG
enhanced tumor
regression [75]
Each row details the nanocarrier type, therapeutic payload(s), intended target/pathway, in vivo cancer model, and main outcomes. PD-1: Programmed cell
death protein 1; PD-L1: programmed death-ligand 1; NP: nanoparticle; CDN: cyclic dinucleotide; STING: stimulator of interferon genes; GMP: good manufacturing
practice; IFN: interferon; TAMs: tumor-associated macrophages; DC: dendritic cell; iRGD: internalizing RGD; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B;
PTEN: phosphatase and tensin homolog; mRNA: messenger RNA; MDSCs: myeloid-derived suppressor cells; PLGA: poly(lactic-co-glycolic acid); siRNA: small
interfering RNA; LCN: lipid-coated calcium phosphate NPs; TNF-α: tumor necrosis factor-α; SLN: solid lipid nanoparticle; HAase: hyaluronidase; shPD-L1: small
hairpin RNA of PD-L1; RAPA: rapamycin; mTOR: mechanistic target of rapamycin; BBB: blood-brain barrier; LAG-3: lymphocyte-activation gene 3; IGU:
Iguratimod; Rh: rhodium; CUR: curcumin; PPC: PDPA-PEG-CDM; NF-κB: nuclear factor kappa B; ICG: indocyanine green; TIME: tumor immune microenvironment.
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