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Bioactive Materials2021ReviewNon-viral Gene Delivery

The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment

Muyue Yang, Jipeng Li, Ping Gu, Xianqun Fan

Summary

Tumor microenvironment (TME) modulation is a promising strategy in cancer immunotherapy, but conventional immunotherapeutic agents suffer from limited drug retention in the TME, severe adverse events, and low response rates. Nanoparticles can prolong retention, enable targeted delivery to TME components, and convert the immunosuppressive TME into an immunosupportive state, potentially improving therapeutic efficacy while reducing toxicity. DC targeting: CD40-targeted PLGA nanoparticles achieved highest binding/uptake and maximum IL-12 production in vitro; however, T cell proliferation was driven mainly by TLR ligands rather than targeting ligand. -.

Keywords

NanoparticlesCancer immunotherapyTumor microenvironmentPLGAChemotherapyT cellsMacrophages
Purpose: Tumor microenvironment (TME) modulation is a promising strategy in cancer immunotherapy, but conventional immunotherapeutic agents suffer from limited drug retention in the TME, severe adverse events, and low response rates. Nanoparticles can prolong retention, enable targeted delivery to TME components, and convert the immunosuppressive TME into an immunosupportive state, potentially improving therapeutic efficacy while reducing toxicity.
Hypothesis: As a review article, this work does not test a single hypothesis. Its central thesis is:

If nanoparticles are engineered to target major TME components—dendritic cells (DCs), tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), tumor vasculature, tumor-draining lymph nodes (tdLNs), and hypoxic regions—then they can modulate the immunosuppressive TME, enhance cancer immunotherapy, and synergize with chemotherapy, radiotherapy, and photodynamic therapy (PDT) to improve anti-tumor outcomes.

Aims: Primary Aim: To review various nanoparticles targeting TME components and their applications in tumor therapy.
  • Secondary Aims:
  • To briefly introduce the major components of the TME, including DCs, macrophages, fibroblasts, tumor vasculature, tdLNs, and the hypoxic state.
  • To summarize how nanoparticles can be designed to target these components and modulate the TME.
  • To discuss the combination of nanoparticle-based TME modulation with other therapies (chemotherapy, radiotherapy, PDT).
  • To highlight challenges and future perspectives for clinical translation.
Delivery system:

Component: Nanoparticle Types; Examples Discussed: PLGA nanoparticles, lipid-coated calcium phosphate nanoparticles, erythrocyte membrane-enveloped nanoparticles, Fe₃O₄ nanoparticles, antigen-capturing nanoparticles (AC-NPs), gold nanocages (AuNCs), liposomes, albumin-based nanoparticles, micelles, nanogels, MnO₂ nanoparticles, perfluorocarbon (PFC)-loaded PLGA nanoparticles, mesoporous silica nanostructures, upconversion nanoparticles, HPMA polymer-based nanovehicles, CaCO₃ nanoparticles, iron nanoparticles

Component: Payloads; Examples Discussed: Tumor antigens (e.g., BRAF^V600E peptide, ovalbumin, hgp100₂₅₋₃₃), TLR ligands/agonists (TLR3, TLR4, TLR7/8, CpG), siRNA (anti-colony stimulating factor-1 receptor, anti-BTK), chemotherapeutics (doxorubicin, paclitaxel, gemcitabine, navitoclax, ibrutinib), photosensitizers (chlorine e6), oxygen (via MnO₂ or PFC), anti-angiogenic agents (LMWH, erlotinib, relaxin-2)

Component: Targeting Ligands/Moieties; Examples Discussed: Antibodies to CD40, DEC-205, CD11c; mannose; hyaluronic acid (HA); sialic acid (for Siglec-1); transferrin receptor-binding peptide T12; SPARC; FAP-specific single-chain variable fragment (scFv); tenascin C-binding peptide FH; anti-CD3; anti-CD8

Component: TME Targets; Examples Discussed: Dendritic cells, tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), tumor vasculature, tumor-draining lymph nodes (tdLNs), hypoxic regions

Component: Routes of Administration; Examples Discussed: Systemic (IV), intratumoral, subcutaneous, intradermal, intraperitoneal

Approach: This is a narrative review synthesizing preclinical and clinical literature. No primary experimental data are presented. The review:
  • Summarizes studies using various nanoparticle platforms in mouse tumor models and cell lines (Table 1).
  • Covers TME components individually: DCs, TAMs, CAFs, tumor vasculature, tdLNs, and hypoxia.
  • Evaluates nanoparticle design parameters such as size, charge, ligand modification, and stimuli-responsiveness.
  • Discusses combination with chemotherapy, radiotherapy, PDT, and checkpoint inhibitors.
  • Includes examples of FDA-approved nanodrugs (Doxil, Abraxane) as context.
Key methods: As a review, the “methods” are literature synthesis and comparative analysis. Headline data cited from primary studies were generated using:
  • Flow cytometry: Immune cell activation, T cell proliferation, DC maturation, M1/M2 polarization.
  • Imaging: In vivo noninvasive fluorescence imaging, photoacoustic bioimaging (AuNCs), MRI (SPIONs).
  • Reporter assays: Luciferase, GFP, IFN-γ, IL-12, TNF-α, IL-10, TGF-β.
  • Tumor efficacy: Tumor volume, survival rate, metastasis nodule count, cure rate.
  • Histology/immunohistochemistry: α-SMA expression, CAF percentage, vessel normalization.
  • Biodistribution: Lymphatic drainage to tdLNs, accumulation in tumor and organs.
Key results: DC targeting: CD40-targeted PLGA nanoparticles achieved highest binding/uptake and maximum IL-12 production in vitro; however, T cell proliferation was driven mainly by TLR ligands rather than targeting ligand. - Antigen-capturing nanoparticles (AC-NPs): Captured multiple tumor-derived protein antigens and achieved 20% cure rate in melanoma models vs. 0% in controls. - TAM repolarization: Ferumoxytol (iron oxide) induced M2→M1 transition, increased H₂O₂ 11-fold and hydroxyl radicals 16-fold, and inhibited tumor growth in a TAM-dependent manner. - M2-targeted siRNA nanoparticles (M2NP): Eliminated 52% of M2 macrophages, decreased tumor size, and increased survival. - CAF targeting: Navitoclax-loaded, tenascin C-targeted nanoliposomes reduced CAF percentage to 18% vs. 77% in controls. - tdLN targeting: Nanoparticles of 10–100 nm showed optimal lymphatic drainage; 40–50 nm antigen-conjugated beads produced 2–10-fold stronger T cell responses than other sizes; 10–22 nm gold nanoparticles induced maximum immune responses. - Melittin-lipid nanoparticles: Increased CD8⁺ T cell responses 3.6-fold, with 95% inhibition of primary tumor growth and 92% inhibition of distant tumor growth. - Vasculature disruption + immunotherapy: PLGA nanoparticles loaded with VDA (DMXAA) and TLR7/8 agonist achieved 63.6% survival vs. 18.1% (PLGA alone) and 9% (DMXAA alone). - Hypoxia relief: PFC-loaded nanoparticles increased tumor oxygenation 3-fold and reduced hypoxic areas; MnO₂ nanoparticles reacted with H₂O₂ to produce oxygen and enhance PDT/chemotherapy.
Interpretation: The authors conclude that nanoparticles offer significant advantages over traditional drug delivery systems: tunability, EPR-based tumor accumulation, spatiotemporal drug release, and ability to target and modulate TME components. By converting the immunosuppressive TME to an immunosupportive state, nanoparticles can enhance cancer immunotherapy and synergize with chemotherapy, radiotherapy, and PDT. However, clinical translation requires deeper understanding of the immune network, tumor heterogeneity, nanoparticle immunogenicity, and long-term safety of TME modulation.
Limitations: Limitations inherent to the review:
  • No primary experimental data; conclusions are synthesized from existing literature.
  • No systematic search strategy or meta-analysis.
  • Focus is primarily on preclinical studies; limited clinical translation data.
  • Heterogeneity of tumor models and nanoparticle designs makes direct comparisons difficult.

Limitations of the field highlighted by the authors:

  • Incomplete understanding of the immune network: The influence of depleting or inhibiting one TME component on the whole network remains unclear; compensatory pathways may upregulate.
  • Individual variations: Tumor heterogeneity and differences in vasculature lead to variable responses to the same nanotherapy.
  • Potential immunogenicity of nanoparticles: Nanoparticles themselves can be antigenic, accelerating clearance and limiting efficacy; robust immune activation may cause hemolysis and thrombogenesis.
  • Long-term risks of TME modulation: Partially changing TME structure or reversing immunosuppression may promote tumor metastasis; long-term effects need investigation.
  • Immature toxicity assays: Physicochemical properties of nanoparticles can change upon reaction with biological substances; final forms and safety must be carefully evaluated.
  • CAF heterogeneity: Certain CAF subsets may be anti-tumorigenic; complete depletion may not be ideal.
  • TAM origin complexity: M1/M2 phenotypes and locally proliferating vs. systemically recruited TAMs coexist; targeting strategies may be limited by this complexity.
  • Need for optimized design: Size, shape, ligands, and other properties require further optimization before clinical translation.

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The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment | Brilliant Blue Biosciences