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

outcomes as a common mode of failure, underscoring the need for methodological improvements and
greater standardization .
[76]
CLINICAL-STAGE NANO-IMMUNOTHERAPY FORMULATIONS EVALUATED WITH PD-1/PD-L1

BLOCKADE
Based on recent clinical studies, nanotechnology-enabled immunotherapy strategies combined with
PD-1/PD-L1 blockade can be broadly categorized into two major classes: (i) systemically administered
cancer vaccines delivered via NPs; and (ii) intratumorally administered particulate formulations intended to
enhance and potentially restore responsiveness to PD-1-based therapy.

The personalized neoantigen mRNA is delivered using LNPs, and is used in combination with the anti-PD-1
monoclonal antibody pembrolizumab for the treatment of PD-1 inhibitor-resistant melanoma. In the
KEYNOTE-942 clinical trial, an open-label, randomized phase IIb study involving patients with cutaneous
melanoma at high risk of recurrence after complete surgical resection, researchers compared adjuvant
treatment with personalized neoantigen mRNA therapy mRNA-4157 (V940) plus pembrolizumab vs.
pembrolizumab alone. The mRNA-4157 (V940) vaccine was encapsulated in LNPs to enable efficient
delivery. Combination therapy prolonged relapse-free survival (RFS), with 18-month RFS rates of 79% and
62%, respectively, while maintaining a manageable safety profile .
[84]

Another example is the combination therapy of virus-like particle (VLP)-based TLR9 ligand vidutolimod
(CMP-001) and anti-PD-1 monoclonal antibody pembrolizumab. In the dose-escalation phase of a phase Ib
clinical trial, patients with advanced melanoma whose disease had progressed after anti-PD-1
immunotherapy received intratumoral vidutolimod, a CpG-A TLR9 agonist formulated using VLPs, together
with intravenous pembrolizumab. The treatment showed an acceptable safety profile, and 25% of patients
achieved durable clinical responses. Notably, tumor volume was reduced not only in injected lesions but also
in noninjected lesions, including visceral metastases .
[85]

In advanced melanoma, intratumoral administration of the nanocomplex BO-112, a poly I:C formulation
complexed with polyethyleneimine, has also been evaluated in combination with intravenous
pembrolizumab in the phase II SPOTLIGHT-203 trial in patients with acquired resistance to PD-1 inhibitors.
In the intention-to-treat population, the independently assessed objective response rate was 25% , including
10% complete response and 15% partial responses. The median time to progression was 3.7 months and an
overall survival probability of 54% at 24 months. Safety was acceptable, with no treatment-related fatal
adverse events reported . Although this trial addresses acquired resistance to PD-1 blockade rather than
[86]
primary resistance, it illustrates how nano-enabled immune stimulation strategies are being explored
clinically in PD-1-refractory populations.

Based on the recent literature, clinical-stage nano-strategies directly designed to counter tumor-intrinsic
resistance pathways, such as Wnt/β-catenin, PTEN/PI3K-AKT, or defects in IFN signaling, remain scarce.
Most pathway-matched nanosystems, including PTEN mRNA NPs, PD-1 membrane decoys, and PD-L1
siRNA NPs, are still at the preclinical stage. This gap highlights the need for biomarker-driven trial designs
and scalable, regulatory-ready formulations.

CONCLUSION
Primary (intrinsic) resistance to PD-1/PD-L1 blockade remains a major barrier to durable responses across
cancer types. Mechanistically, primary resistance can arise from tumor intrinsic alterations (e.g., defects in
IFN signaling, PTEN loss with PI3K/AKT activation, or Wnt/β-catenin-associated immune exclusion) and

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