Improving Cancer Immunotherapy Outcomes using Biomaterials

Purpose: Cancer immunotherapy has improved clinical outcomes, but few patients show adequate response rates and long-term responses, and systemic side effects remain common due to the dynamic nature of the immune system. Biomaterial-assisted immunotherapy is a promising approach to improve therapeutic efficacy and reduce side effects. ---

Hypothesis: No formal testable hypothesis is proposed. The central thesis is: if rationally designed biomaterials are used to modulate the immune system, deliver immunomodulators, or alter the tumor microenvironment, then cancer immunotherapy outcomes—including CAR T-cell therapy, cancer vaccines, and immune checkpoint blockade—can be improved while reducing toxicity. ---

Aims: - Highlight rationally designed biomaterials that synergize with immunotherapies. - Review biomaterials for improving adoptive cell therapy, cancer vaccine therapy, and immune checkpoint blockade therapy. - Cover organic, inorganic, cell-based, bacteria/virus-based, carbon-based, silica-based, metal-based, MOF, upconversion nanocrystal, and hydrogel platforms. - Discuss limitations of conventional cancer immunotherapies and how biomaterials address them. - Summarize recent advances and outline future directions for biomaterial-assisted immunotherapy. ---

Delivery system: Biomolecule-based materials: nucleic acids (CpG, cGAMP), peptides, proteins, carbohydrates; DNA-RNA nanocapsules; albumin-based in vivo assembly; nanovaccines with antigen/adjuvant. Polymer-based materials: PLGA, chitosan, polyethyleneimine, pH-responsive polymers, micelles, polymer–drug conjugates, polymeric nanoparticles, microneedle patches, scaffolds. Lipid-based materials: liposomes, lipid nanoparticles, high-density lipoprotein nanodiscs, hollow lipid nanoparticles; payloads include antigens, adjuvants, sonosensitizers, checkpoint inhibitors. Cell-based materials: engineered platelets, NK cell membranes, tumor cell-derived vesicles/membranes, CAR T cells, exosomes. Bacteria and viruses: oncolytic viruses, bacterial membranes, microbiome modulation, viral vaccine carriers. Carbon-based materials: nanotubes, graphene oxide, quantum dots, nanodiamonds. Silica-based materials: mesoporous silica nanoparticles, hollow mesoporous silica nanospheres, mesoporous organosilica hollow spheres, mesoporous silica microrods, injectable silica rod scaffolds. Metal-based materials: gold nanoparticles, iron oxide nanoparticles, manganese dioxide nanoparticles, ferumoxytol. Metal–organic frameworks (MOFs): porphyrin-based MOF nanosheets, hafnium-containing MOFs, IDO inhibitor loading. Upconversion nanocrystals (UCNPs): lanthanide-doped UCNPs, photosensitizer-loaded UCNP–polymer hybrids, mesoporous silica-coated UCNPs. Hydrogels: fibrin gel, immunotherapeutic gel, injectable hydrogels, 3D networks for local delivery. Payloads: antigens, neoantigens, adjuvants (CpG, cGAMP, R837), cytokines (IL-15 superagonist, IL-2), checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-CD47), photosensitizers, sonosensitizers, chemotherapeutics, siRNA, mRNA, gene-editing components, imaging agents. Targeting/functional elements: tumor-targeting peptides (e.g., avβ6-targeting HK peptide), antibodies, cell membranes, pH-responsive groups, MMP-9-cleavable peptides, disulfide bonds, catalase, hyaluronic acid, PEG. ---

Approach: Narrative minireview of preclinical and clinical literature. No primary experimental groups. Model systems discussed include: - In vitro: dendritic cells, T cells, macrophages, antigen-presenting cells, tumor cells. - In vivo: mouse models including B16F10 melanoma, 4T1 breast cancer, CT26 colorectal cancer, TC-1, murine breast and colorectal cancer metastasis models, pancreatic cancer, lung cancer, and postsurgical tumor models. - Disease context: cancer immunotherapy, including adoptive cell therapy (CAR T, TCR T, CAR-NK), immune checkpoint blockade, and cancer vaccines. - Clinical context: approved checkpoint inhibitors and clinical trials are referenced, but the review does not perform systematic clinical meta-analysis. ---

Key methods: Techniques highlighted across cited studies: - Flow cytometry for immune cell subsets, T cell responses, and cytokine production. - TEM/SEM imaging for nanoparticle and scaffold characterization. - Luminescence/fluorescence imaging for dendritic cell tracking and biodistribution. - ELISA/cytokine secretion assays. - Tumor growth inhibition, metastasis quantification, and survival analysis. - In vivo mouse tumor models and postsurgical recurrence models. - Photothermal/photodynamic/sonodynamic therapy with laser or ultrasound stimulation. - X-ray radiotherapy–radiodynamic therapy with MOF nanosheets. - Macrophage polarization assays (M1/M2). - Antibody response and T cell proliferation assays. ---

Key results: - DNA–RNA nanocapsules: augmented neoantigen-specific peripheral CD8+ T cell responses more than 8-fold relative to CpG controls and prevented growth of neoantigen-specific colorectal tumors. - Nanovaccine: OVA/ICG nanovaccines showed high antigen-loading efficiency of 80.8% and enabled imaging-guided photothermal immunotherapy. - STING nanoparticles: pH-responsive polymer nanoparticles delivering cGAMP potently inhibited B16F10 growth by stimulating an immunogenic, T-cell-inflamed tumor microenvironment. - Liposome platform HMME/R837@Lip: combined with checkpoint blockade inhibited tumor growth and metastases in 4T1 and CT26 tumor models with high efficacy. - Mesoporous silica microrods: IL-2-functionalized mesoporous silica microrods promoted greater expansion of therapeutic ex vivo T cells compared with commercial expansion beads. - MOF nanosheets: DBP-hafnium MOFs loaded with IDO inhibitor almost completely inhibited tumors in murine breast and colorectal cancer metastasis models under X-ray irradiation. - Ferumoxytol: FDA-approved iron supplement delayed early mammary growth and inhibited lung cancer metastasis by inducing pro-inflammatory macrophage polarization. - Postsurgical fibrin gel: anti-CD47 antibody-loaded CaCO3 nanoparticles in fibrin gel suppressed tumor recurrence and metastasis by polarizing tumor-associated macrophages to M1-like phenotypes and blocking “don’t eat me” signals. - Engineered platelets: PD-L1 antibody-decorated platelets inhibited cancer recurrence and metastatic spread in postsurgical melanoma and breast carcinoma mouse models. ---

Interpretation: The authors conclude that biomaterials play indispensable roles in cancer immunotherapy, including vaccines, CAR T-cell therapy, and checkpoint blockade. Biomaterials ranging from small molecules and nanoparticles to viruses, bacteria, and macroscale scaffolds offer different functions and advantages to enhance antitumor immunity. Hybrid therapies are likely more effective than monomodal therapies because of the complex, immunosuppressive tumor microenvironment. Future biomaterials should target specific tissues or cells, modulate immunity with improved precision at minimal doses, and reduce toxicity and side effects. Processing, quality control, and cross-disciplinary partnerships in chemistry, materials, biomedicine, bioengineering, and clinical medicine will be required for next-generation biomaterials. ---

Limitations: - Review, not primary study: No original experimental data; synthesizes published literature. - Limited clinical translation: Many biomaterials improve outcomes in murine models, but clinical application remains limited. - Safety concerns: Long-term safety of inorganic materials requires comprehensive evaluation, including biodistribution, excretion, metabolism, degradation, and stability. - Immune microenvironment interactions: Interactions between inorganic materials and the immune microenvironment are not fully understood; effects on spleen and lymphoid tissues need further study. - Delivery specificity: Polymer specificity for tumor sites and T cells is insufficient, leading to unsatisfactory therapeutic outcomes. - Lipid limitations: Organic solvents/high temperatures may denature macromolecules; lipid carbon chain lengths are inhomogeneous; electronegativity reduces adjuvant loading; lack of tumor targeting; poor storage stability. - Hydrogel limitations: Chronic inflammatory reactions may emerge during degradation; hydrogels must persist at application sites for sufficient periods but may damage normal organ function. - Cell-based limitations: CAR T-cell therapy is time-consuming and costly, with few positive outcomes; cell vesicle side effects such as potential carcinogenesis require systematic investigation. - Bacteria/virus limitations: Mechanisms of selective tumor targeting and destruction without harming normal tissues remain incompletely understood; administration routes and biodistribution need optimization. - Manufacturing: Processing and quality control of newly designed biomaterials at commercial scales require careful development.