For decades, biomaterials in medicine were conceived as inert scaffolds or passive delivery vehicles, designed to ferry drugs to their targets while provoking as little immune reaction as possible. That paradigm has inverted. The review highlights how materials spanning inorganic nanoparticles, synthetic polymers, natural biomacromolecules, and cell-derived vesicles are now deliberately designed to engage and reprogram macrophages, dendritic cells, T lymphocytes, and innate lymphoid cells. Because these materials can act as immune activators or suppressors depending on their chemistry, size, shape, and context, they offer a versatile platform for treating inflammation, cancer, infection, and autoimmune disease. The authors emphasize that targeted drug delivery and immuno-engineering are only part of the story; the intrinsic immunomodulatory properties of the materials themselves must not be overlooked.

Inorganic nanomaterials occupy a prominent place in this landscape because of their superior physicochemical stability and controllability. Their non-self nature means the immune system recognizes them as foreign, activating phagocytic cells such as macrophages and dendritic cells. While this inflammatory response would be undesirable in healthy tissue, it can paradoxically enhance tumor immunotherapy. Gold nanorods, fullerene derivatives, and graphene oxide derivatives have all demonstrated capacity as vaccine adjuvants, inducing localized inflammation that strengthens immune protection against viral infections and malignancies. A particularly intriguing subset, known as nanozymes, exhibits intrinsic enzyme-like catalytic activity whose output depends on particle size, structure, cellular internalization, and environmental pH, allowing them to either raise or lower reactive oxygen species concentrations in chronic inflammatory microenvironments.

Iron oxide nanoparticles illustrate the clinical maturity of this approach. Several formulations have already been approved by the U.S. Food and Drug Administration as magnetic resonance imaging contrast agents, treatments for iron deficiency, and components of nano-vaccine platforms. Beyond these established uses, studies show that iron oxide nanoparticles can drive M1 polarization of macrophages, boosting production of reactive oxygen species, tumor necrosis factor-alpha, and nitric oxide to inhibit tumor progression. In one reported mechanism, uptake of these particles by macrophages raises intracellular iron and activates the NF-κB signaling pathway, triggering TNF-α-mediated immune activation. The particles also display enzyme-like behavior: ultrasmall Fe₃O₄ nanoparticles act as peroxidases under acidic conditions, decomposing hydrogen peroxide into hydroxyl radicals that kill cancer cells, while a catalase-mimicking material called fenozyme has reduced mortality in experimental cerebral malaria by lowering reactive oxygen levels and promoting macrophage polarization.

Manganese-based nanomaterials have emerged as equally potent immunological tools. Manganese ions markedly enhance the sensitivity of the cGAS–STING pathway, a central innate immune sensor that recognizes microbial and endogenous DNA. Research cited in the review shows that Mn²⁺ increases antigen presentation by dendritic cells and macrophages, facilitating activation of natural killer cells and T lymphocytes, and that combining this effect with anti-PD-1 checkpoint blockade yields notable therapeutic efficacy. Researchers have also developed coordination nanoparticles that self-assemble from manganese ions and a STING agonist, producing enhanced interferon responses and robust antitumor immunity in treatment-resistant tumor models, and manganese-based nano-vaccines have shown promise in preclinical models of SARS-CoV-2 infection. Other metal systems extend the catalog: nanoscale titanium dioxide with nanospike structures exerts mechanical stress on phagocytosing immune cells, triggering potassium efflux and inflammasome activation, while ultrasmall copper oxide nanozymes scavenge reactive oxygen species and ameliorate acute liver injury, diabetic wounds, and acute kidney injury.

Silicon nanoparticles tell a story of transformation from hazard to therapeutic. Unmodified silica can provoke inflammatory responses through interactions with monocytes and the complement system, and accumulation of silica dioxide particles in lung tissue has been shown to create a premetastatic niche in healthy mice. Yet in tumor-bearing organisms this immunostimulatory character becomes an asset. Ultrasmall silica nanoparticles can initiate T cell activation through direct particle–cell interactions in a dose-dependent manner, and certain formulations have progressed to human clinical trials. Hollow mesoporous silica nanoparticles function as immunoadjuvants that enhance both Th1 and Th2 responses, elevate effector memory T cell populations in the bone marrow, and, remarkably, when administered intraperitoneally, significantly improve the response to PD-1 checkpoint blockade by targeting tumor-associated macrophages, activating the Toll-like receptor 4–NF-κB cascade, and increasing secretion of T cell–recruiting chemokines. For immunologically cold tumors, this strategy of amplifying local inflammation is compelling.

Carbon-based nanomaterials present a more complicated picture. Graphene oxide acts as a natural antioxidant, reducing reactive oxygen species in macrophages and mitigating M1 polarization, and graphene quantum dots have suppressed Th1/Th17 polarization, promoted regulatory T cell ratios, and alleviated intestinal inflammation in murine models of enteritis. These quantum dots can even cross the blood–brain barrier and inhibit aggregation of alpha-synuclein fibrils, suggesting neuroprotective potential in Parkinson’s disease. However, concerns about carcinogenicity, particularly for carbon nanotubes, temper enthusiasm; prolonged exposure to multiwalled carbon nanotubes has been reported to intensify the invasiveness of implanted breast cancer cells and promote lung colonization. This duality, in which the same inflammatory capacity that makes a material a useful adjuvant can also pose long-term risks, remains one of the field’s central unresolved problems.

Organic and cell-derived biomaterials offer biocompatibility advantages that inorganic systems struggle to match. Synthetic polymer hydrogels have been engineered to initiate type-2 adaptive immune responses that promote skin regeneration, and acid-responsive polymeric nanoparticles that target lymph nodes and activate the STING pathway have spawned optimized, degradable successors. Cationic nanoparticles composed of PLGA–PDMA block copolymers can scavenge cell-free DNA, reducing inflammatory activation in rheumatoid arthritis models. Natural biomacromolecules carry inherent activity: fungal polysaccharides, yeast cell wall beta-glucans, and hyaluronic acid all modulate macrophage polarization and T cell responses, with hyaluronic acid’s effects shifting depending on molecular weight. DNA nanostructures built through programmable base pairing can deliver CpG oligonucleotides, potent Toll-like receptor 9 agonists, into immune cells with high specificity, and a rectangular DNA origami nanorobot decorated with immune agonists has trafficked to draining lymph nodes and evoked durable tumor-specific immune responses. Perhaps most striking are cell membrane-coated nanoparticles: mesenchymal stem cell membranes displaying PD-L1 have suppressed excessive T cell activation and eased immune-related adverse events from checkpoint blockade, macrophage membrane nanosponges have sequestered inflammatory cytokines in atherosclerosis and sepsis models, and fusion nanodecoys combining ACE2-expressing membranes with monocyte membranes have simultaneously neutralized virus and absorbed cytokines in COVID-19 research. Exosomes, the nanoscale vesicles cells use to communicate, add another layer, with phenotype-dependent functions ranging from tumor repolarization to insulin sensitization.

The review’s authors are candid about the obstacles standing between laboratory promise and clinical routine. Incomplete degradation, unintended biodistribution, and persistent low-grade inflammation may lead to fibrosis, granuloma formation, or off-target immunotoxicity, demanding long-term in vivo studies and standardized evaluation protocols. Inorganic materials raise questions about ion release and oxidative stress during degradation, while polymers suffer from batch-to-batch variability and complex manufacturing that hinders scalability. Exosome production remains inefficient and heterogeneous, and endotoxin contamination, even at trace levels, can confound experimental results entirely. Looking forward, the authors point to single-cell sequencing, spatial transcriptomics, and artificial intelligence-driven material screening as technologies that could illuminate how biomaterials shape immune microenvironments and accelerate rational design. They also envision personalized immunomodulatory biomaterials tailored to individual immune profiles, and feedback-responsive systems capable of achieving controlled, localized, transient immune activation without systemic toxicity. If those challenges can be met, the materials described in this synthesis may do more than carry the next generation of immunotherapies; they may become the therapies themselves, precisely engineered to teach the immune system when to fight and when to stand down.

Subject of Research: Immunomodulatory biomaterials for immunotherapy

Article Title: Advances and projects of immunomodulatory biomaterials used for immunotherapy

Article References: Frumento, D., & Patra, N. (2026). Advances and projects of immunomodulatory biomaterials used for immunotherapy. Holistic Integrative Oncology, 5(1), Article 78. https://doi.org/10.1007/s44178-026-00296-3

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00296-3

Keywords: immunomodulatory biomaterials, immunotherapy, nanozymes, iron oxide nanoparticles, manganese adjuvants, STING pathway, mesoporous silica nanoparticles, graphene quantum dots, cell membrane-coated nanoparticles, exosomes, macrophage polarization, cancer immunotherapy

The clinical backdrop makes the finding consequential. Hypopharyngeal squamous cell carcinoma, which arises in the region of the throat surrounding the larynx, is among the most lethal head and neck malignancies, with survival rates that have remained stubbornly poor for decades. Induction chemotherapy, typically built around the platinum drug cisplatin, is a cornerstone of treatment because it can shrink tumors enough to permit organ-preserving surgery or definitive radiation. Yet the strategy carries an inherent gamble: if resistance develops, the window for effective intervention narrows dramatically. Understanding why some tumors evolve resistance while others remain sensitive has therefore been a central question, and the mechanisms of acquired resistance to induction chemotherapy in this disease had remained incompletely mapped until now.

To interrogate that question at the genomic level, the team turned to a rare and valuable resource: paired tissue samples from nine patients with hypopharyngeal squamous cell carcinoma who had shown an initial complete or strong response to induction chemotherapy and then progressed. Because the archived paraffin-embedded specimens from both time points were available, the researchers could perform whole exome sequencing on the pre-treatment tumor and its recurrent descendant from the same patient, effectively watching tumor evolution in action. The comparison revealed that two-thirds of the patients, six of the nine, had acquired novel mutations during progression that were not detectable in their original tumors. This pattern of newly emerged variants is the genomic fingerprint of Darwinian selection, in which therapy eliminates susceptible cells and spares those rare clones carrying mutations that confer a survival advantage.

Among the newly emerged alterations, changes in three genes drew particular attention for their potential functional relevance: ENPP1, ALK, and ATP10B. But it was ENPP1 that dominated the analysis. Mutations in this gene were present in half of the six patients who had acquired new variants during progression, a striking enrichment for a single gene in so small a cohort. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, a membrane-bound enzyme best known in cancer biology for its ability to degrade 2’3′-cGAMP, the small signaling molecule that activates the STING pathway, a critical arm of innate immune sensing. Previous work in breast cancer and other tumor types had already implicated ENPP1 as a kind of innate immune checkpoint, allowing tumors to dampen the cGAS-STING alarm system that would otherwise flag them for immune destruction.

To move from correlation to causation, the researchers built a functional toolkit in the laboratory. Using CRISPR-Cas9-mediated knockout, they deleted ENPP1 from hypopharyngeal cancer cells and observed that its loss suppressed the malignant phenotypes that define aggressive disease, including proliferative capacity and survival under stress. Conversely, when they introduced the specific mutant variant found in the patients, a single nucleotide change designated c.2596 G > C that swaps a glutamine for a glutamic acid at position 866 of the protein, the effect reversed dramatically. Cells engineered to express mutant ENPP1 became markedly more resistant to cisplatin, the workhorse drug of induction regimens. The mutation also enhanced the enzyme’s hydrolysis of 2’3′-cGAMP, meaning the mutant protein was not merely a passive passenger but an actively more capable destroyer of the immune-activating messenger molecule.

The mechanistic thread connecting these observations runs through the STING pathway, and the study’s findings here are notable for their apparent paradox. Rather than simply shutting STING down, ENPP1 mutation was associated with sustained activation of STING, accompanied by enhanced signaling through the transcription factor NF-κB and elevated production of interleukin-6, a pro-inflammatory cytokine with well-documented roles in tumor cell survival. This matters because STING is a double-edged sword in cancer immunology. In one context, its activation recruits immune cells and sensitizes tumors to immunotherapy; in another, chronic STING engagement drives NF-κB and IL-6 signaling that promotes survival of genomically unstable cancer cells, a phenomenon documented in prior studies of chromosomally unstable cancers and triple-negative breast cancer. The Fudan team’s data suggest that in hypopharyngeal carcinoma, the mutant enzyme tilts STING signaling toward the pro-survival, inflammatory branch rather than the anti-tumor interferon response.

The in vivo evidence strengthened the case considerably. When the researchers tested the mutant ENPP1 in xenograft models, transplanting engineered tumor cells into mice, the mutation increased tumorigenic capacity, meaning tumors carrying the mutant gene grew more aggressively. Critically, those xenografts also displayed resistance to cisplatin treatment, confirming that the mutation’s effects were not artifacts of cell culture but translated into treatment failure in living tissue. Together, the in vitro and in vivo experiments establish ENPP1 mutation as a functional driver of both enhanced malignancy and chemotherapy resistance, satisfying the criteria that molecular oncologists typically demand before accepting a gene as a genuine therapeutic target rather than a bystander in tumor evolution.

The implications extend beyond cisplatin resistance into the realm of immunotherapy and treatment sequencing. Because ENPP1 mutations mediate what the authors describe as both chemotherapy resistance and immunomodulation, the finding suggests that recurrent tumors carrying these alterations may exist in a distinctly different immune microenvironment than their treatment-naive ancestors. If mutant ENPP1 reshapes STING signaling and IL-6 production, it could influence how recurrent hypopharyngeal cancers respond to immune checkpoint inhibitors, which are increasingly used in head and neck cancer. It also raises the prospect of therapeutic intervention at the ENPP1 enzyme itself; small-molecule ENPP1 inhibitors are under active development in other tumor contexts, and this study provides a rationale for evaluating them in hypopharyngeal carcinoma, potentially in combination with platinum chemotherapy to prevent or delay the emergence of resistant clones.

Caveats remain, as they must in any study of this scale. Nine patients is a small cohort, and the retrospective design means the findings require validation in larger, prospective series before ENPP1 mutation testing could enter clinical decision-making. The data underlying the study are not publicly available due to privacy and ethical considerations but can be obtained from the corresponding authors upon reasonable request, and the work was approved by the ethics committee of the Eye and ENT Hospital of Fudan University with informed consent from all participants. Still, the study’s central contribution is conceptual as much as practical: it demonstrates that the seeds of relapse are written in the genome during treatment, and it names a specific, druggable culprit. For patients whose tumors vanish on scan only to return with lethal defiance, that molecular clarity is the first step toward intercepting resistance before it takes hold.

Subject of Research: ENPP1 mutation-driven cisplatin resistance through the STING/NF-κB/IL-6 axis in hypopharyngeal squamous cell carcinoma

Article Title: From initial complete response to recurrence: ENPP1 mutation drives cisplatin resistance through STING/NF-κB/IL-6 axis in hypopharyngeal squamous cell carcinoma

Article References: Hu, C., Liu, X., Yuan, C., Zhang, L., Yang, R., Liu, R., Xiang, W., Yang, R., Hu, Q., Yu, M., Chen, J., Huang, Q., Ma, D., & Zhang, J. (2026). From initial complete response to recurrence: ENPP1 mutation drives cisplatin resistance through STING/NF-κB/IL-6 axis in hypopharyngeal squamous cell carcinoma. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03625-5

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03625-5

Keywords: ENPP1, cisplatin resistance, hypopharyngeal squamous cell carcinoma, STING pathway, NF-κB, IL-6, whole exome sequencing, tumor recurrence, induction chemotherapy, cGAMP, head and neck cancer, CRISPR-Cas9