Role of nanotechnology in modulating the tumor microenvironment to enhance immunotherapy efficacy

Abstract

The immunosuppressive tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is marked by hypoxia, acidity, and abundant stromal cells, such as cancer-associated fibroblasts, tumor-associated macrophages, and myeloid-derived suppressor cells, along with factors such as tobacco and alcohol exposure, human papillomavirus infection, and microbial imbalance that drive immune evasion and poor immunotherapy responses. This review critically evaluated nanotechnology-driven strategies for reprogramming the OSCC TME, focusing on overcoming immunosuppression, hypoxia, stromal barriers, and OSCC-specific challenges to enhance immunotherapy outcomes. Personalized nanotherapies guided by TME profiling, combination with radiotherapy/chemotherapy, and theranostic nanoparticles show promise despite manufacturing/regulatory challenges. Nanotechnology enables transformative TME reprogramming to potentiate OSCC immunotherapy, necessitating interdisciplinary research and clinical validation.

Key Words: Immunotherapy; Oral squamous cell carcinoma; Nanomedicine; Tumor microenvironment; Tumor associated macrophages; Hypoxia; Nanoparticles

Core Tip: Oral squamous cell carcinoma exhibits a highly immunosuppressive tumor microenvironment (TME) that severely limits immunotherapy efficacy. This review highlighted how nanotechnology offers transformative strategies to overcome key TME barriers. Specifically, engineered nanoparticles can reprogram tumor-associated macrophages, alleviate hypoxia via oxygen-generating carriers, disrupt cancer-associated fibroblasts and extracellular matrix, and deliver targeted therapies (e.g., human papillomavirus E6/E7 small interfering RNA). Oral squamous cell carcinoma-tailored approaches also counteract carcinogen-induced oxidative stress and microbiota-driven immunosuppression. These innovations enable precise TME remodeling to enhance immune cell infiltration and checkpoint inhibitor performance, representing a paradigm shift towards improving clinical outcomes in oral cancer immunotherapy.

INTRODUCTION

Oral squamous cell carcinoma (OSCC) represents a major global public health challenge with particularly high incidence and mortality rates in South and Southeast Asia where it ranks among the most prevalent malignancies. The disease is often diagnosed at an advanced stage, contributing to a 5-year survival rate of less than 50%[1]. In recent years, immunotherapy has emerged as a critical treatment modality for OSCC; however, the highly complex tumor microenvironment (TME) necessitates personalized therapeutic strategies guided by biomarkers, such as programmed death-ligand 1 (PD-L1) expression and tumor mutational burden[2,3].

The OSCC TME comprises a heterogeneous network of immune and stromal cells, diverse cytokines, and extracellular matrix (ECM) components. It is further characterized by hypoxia, acidic pH, and elevated interstitial fluid pressure, all of which contribute to immune evasion and diminish the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors (ICIs)[4]. Metabolic constraints within the TME, such as low oxygen levels, acidosis, and nutrient depletion, further impair immune cell activity. Targeting these barriers with hypoxia-inducible factor (HIF) inhibitors or metabolic modulators has shown potential to enhance immunotherapy outcomes[5].

Additionally, abnormal tumor vasculature limits both immune cell infiltration and drug delivery; however, antiangiogenic therapies can normalize blood vessels, thereby improving immune cell access and treatment effectiveness[6]. Disruption of the tumor stroma, including cancer-associated fibroblasts (CAFs) and ECM, can further facilitate immune cell penetration into tumor tissues[7]. The combination of immunotherapy with chemotherapy or radiotherapy may produce synergistic effects by inducing immunogenic cell death and eliminating immunosuppressive cell populations[8,9]. Recent advances in single-cell sequencing and spatial transcriptomics have paved the way for individualized TME profiling, enabling more precise and patient-specific therapeutic interventions[10]. Reprogramming the TME to favor antitumor immunity is now recognized as a cornerstone of modern cancer immunotherapy and holds considerable promise for improving clinical outcomes in patients with cancer.

Nanotechnology has emerged as an innovative approach for the targeted and precise modulation of the TME, offering new strategies to increase the effectiveness of immunotherapy. Nanoparticles can be engineered to deliver therapeutic agents, including ICIs, cytokines, and small-molecule drugs, directly to the TME, minimizing off-target effects and systemic toxicity[11]. For example, nanocarriers can be designed to respond to TME-specific stimuli, such as low pH or tumor-associated enzymes, ensuring localized and controlled drug release[12]. Furthermore, nanoparticles can selectively target distinct cell populations within the TME, such as tumor-associated macrophages (TAMs) or CAFs, to reprogram immunosuppressive cells into a proinflammatory phenotype[13]. Nanotechnology platforms can also codeliver multiple agents, such as ICIs with chemotherapeutic drugs or metabolic inhibitors, to synergistically enhance antitumor immunity[14]. Functionalization with ligands or antibodies further increases the specificity of nanoparticle accumulation in tumor or immune cells within the TME[15]. For instance, gold nanoparticles and liposomes have been used to transport small interfering RNA (siRNA) or CRISPR/Cas9 components to silence immunosuppressive genes and improve the performance of immune cells[16]. Additionally, nanotechnology enables advanced imaging and real-time monitoring of TME modulation, thereby supporting adaptive and personalized treatment strategies[17].

Overall, nanotechnology provides a versatile and promising platform for overcoming the key barriers in cancer immunotherapy through targeted TME reprogramming. This review critically examined the current advances in nanotechnology for remodeling the OSCC TME to improve immunotherapy outcomes.

TME IN ORAL CANCER

The TME is an intricate system composed of diverse cellular and non-cellular elements that dynamically interact with tumor cells to regulate cancer growth, immune escape, and treatment resistance. Among its key cellular constituents are CAFs, which arise from benign fibroblasts or mesenchymal stem cells or through epithelial-mesenchymal transition (EMT). CAFs can constitute up to 80% of the TME and are highly heterogeneous, influencing tumor growth, invasion, and therapy resistance[18]. They can be further categorized into subtypes such as myofibroblastic CAFs and inflammatory CAFs, each playing specific roles in tumorigenesis and immune modulation. CAFs actively remodel the ECM, promote angiogenesis, and secrete cytokines, chemokines, and growth factors, including transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and interleukin (IL)-6. These factors support tumor invasion and growth and contribute to immune suppression by activating regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), creating both physical and biochemical barriers that restrict immune cell infiltration and therapeutic agent delivery[19]. CAFs also release extracellular vesicles that facilitate tumor progression and immune evasion[20].

Tregs suppress antitumor immunity through various mechanisms, including secretion of immunosuppressive cytokines such as TGF-β and IL-10 and expression of ICI molecules like PD-1. Tregs can also interact directly with CAFs, further reinforcing immunosuppressive effects[21,22]. MDSCs, a heterogeneous population of immature myeloid cells, accumulate in the TME and play a central role in dampening immune responses. They suppress T cell activity by metabolizing L-arginine, producing reactive oxygen species (ROS), and releasing immunosuppressive cytokines[23,24].

The TME also contains immune cells that frequently polarize towards protumor functions. Among the most notable are TAMs, which can adopt either M1 (antitumor) or M2 (protumor) phenotypes[25,26]. In most tumors TAMs predominantly shift to the M2 phenotype, producing immunosuppressive cytokines such as IL-10 and TGF-β, promoting angiogenesis via VEGF, and inhibiting cytotoxic T cell function. Similarly, Tregs inhibit antitumor immunity by suppressing effector T cells and natural killer cells through the secretion of IL-10 and TGF-β[27]. MDSCs further strengthen immune suppression by blocking T cell activation and supporting Treg proliferation while secreting ROS, nitric oxide, and arginase-1 to establish an immunosuppressive microenvironment[24,28].

Another critical component of the TME is the ECM, which consists of structural proteins such as collagen, fibronectin, and laminin along with proteoglycans and glycoproteins. The ECM provides mechanical support for tumors and acts as a reservoir for growth factors[29]. In cancer CAFs and TAMs restructure the ECM, creating a stiff, dense fibrotic barrier known as desmoplasia. This abnormal ECM architecture promotes tumor invasion and metastasis and functions as a physical barrier that restricts immune cell infiltration and drug penetration. For example, the ECM can sequester cytokines like IL-2, reducing their availability to effector T cells, and can attract immunosuppressive cells such as TAMs and MDSCs[27].

TME-associated cytokines and chemokines coordinate complex signaling networks that regulate immune modulation, angiogenesis, and metastasis. Tumor-promoting cytokines such as IL-6, IL-10, and TGF-β drive immune evasion and EMT, whereas proinflammatory cytokines like TNF-α and IL-1β induce chronic inflammation that support tumor growth[30]. Chemokines such as CXCL12 recruit suppressor cells and endothelial progenitors, promoting neovascularization and tumor progression. Cytokines modulate immune cell function by binding to specific receptors and triggering signaling cascades; for example, TGF-β supports macrophage polarization towards the M2 TAM phenotype and enhances Treg expansion while chemokines like CCL19 and CCL21 attract immune cells into defined TME niches[31].

Hypoxia is another hallmark of solid tumors and plays a major role in shaping the TME. Rapid tumor cell proliferation often outpaces the available oxygen supply, producing extensive hypoxic zones[32]. Under hypoxia HIF-1α and HIF-2α stabilize, initiating pathways that upregulate VEGF to drive angiogenesis, increase glycolysis, and promote immune evasion by recruiting Tregs and favoring M2 TAM polarization. Hypoxia also induces metabolic reprogramming that helps tumor cells adapt to low-oxygen conditions and enhances their invasive potential[33].

In summary, the TME is composed of diverse cellular and molecular components that collectively promote tumor progression, immune escape, and resistance to treatment. These features can contribute to both primary and acquired resistance to immunotherapy, highlighting the need for effective strategies to modulate the TME and improve clinical outcomes (Table 1).

Table 1 Key tumor microenvironment components, their roles, and therapeutic targets.

Component	Role in TME	Therapeutic targets
CAFs	Promote tumor growth, immune evasion, and ECM remodeling	Targeting biglycan, inhibiting CAF signaling pathways, or depleting CAFs
TAMs	Promote tumor progression, angiogenesis, and immune suppression	Targeting the CSF1/CSF1R axis or inhibiting TAM polarization
Tregs	Suppress antitumor immunity and promote tumor growth	Targeting the IL-2/IL-2R axis or inhibiting Treg function
MDSCs	Inhibit T cell function and promote immune suppression	Targeting ARG1 or inhibiting MDSC recruitment
ECM	Acts as a physical barrier and modulates immune cell function	Targeting ECM components such as collagen or hyaluronan
Cytokines	Regulate immune cell function and promote immune evasion	Targeting TGF-β signaling or enhancing proinflammatory cytokines
Hypoxic conditions	Promote immune suppression and tumor progression	Targeting HIF signaling, enhancing oxygenation, or inhibiting adenosine-generating enzymes

TME: Tumor microenvironment; CAFs: Cancer-associated fibroblasts; TAM: Tumor-associated macrophages; HIF: Hypoxia-inducible factor; Tregs: Regulatory T cells; MDSCs: Myeloid-derived suppressor cells; ECM: Extracellular matrix.

For instance, in non-small cell lung cancer, alterations within the TME including driver mutations, modulation of T cell infiltration, and enrichment of M2 TAMs are key contributors to primary resistance to immunotherapy. Acquired resistance mechanisms in non-small cell lung cancer involve changes in cell infiltration patterns and dysregulation of interferon signaling pathways[34]. In breast cancer cellular components such as CAFs and MDSCs actively shape the TME in ways that promote resistance to immunotherapy. Strategies to counteract this resistance include reprogramming CAFs and modulating TAM polarization[35]. In colorectal cancer liver metastasis, TGF-β plays a central role in generating an immunosuppressive TME that limits cytotoxic T lymphocyte infiltration and facilitates immune escape. Targeting TGF-β can potentially reprogram the TME, enhance antitumor immune responses, and improve ICI efficacy[36]. The TME also governs the balance between costimulatory and inhibitory pathways in tumor-infiltrating lymphocytes, thereby modulating T cell activation and exhaustion states[37]. Understanding these complex interactions has revealed new therapeutic targets for reprogramming the TME to restore effective antitumor immunity. Inhibiting these components, either alone or in combination with existing immunotherapies, holds promise for improving cancer treatment outcomes.

OSCC-specific TME features

The TME of OSCC exhibits several unique features that distinguish it from other solid tumors and significantly influence disease progression and therapeutic response. A major contributing factor is exposure to site-specific carcinogens such as tobacco and alcohol. Chronic tobacco use generates ROS and carcinogenic metabolites that cause sustained epithelial injury, activate fibroblasts, and promote ECM remodeling[1]. This results in increased fibrotic tissue deposition and a stiffer ECM, which facilitates tumor invasion and creates a physical barrier to immune cell infiltration[19]. Tobacco and alcohol exposure also modulate cytokine expression profiles within the TME, elevating levels of immunosuppressive mediators such as TGF-β and IL-6, which further promote the recruitment of Tregs and MDSCs[7,23]. Additionally, acidosis (pH 6.5) is more pronounced in OSCC due to enhanced glycolytic metabolism and poor perfusion. In this context pH-responsive nanoparticles (e.g., chitosan-based carriers) can be employed to release therapeutic agents in acidic environments. Antioxidant nanoparticles (e.g., cerium oxide) can neutralize ROS while oxygen-generating nanocarriers (e.g., perfluorocarbon nanoparticles) can alleviate hypoxia[38-40].

Another critical aspect of OSCC pathogenesis is its association with oncogenic viruses, particularly human papillomavirus (HPV). HPV-positive OSCCs differ biologically from HPV-negative tumors and are characterized by higher infiltration of immune cells (e.g., CD8+ T cells and dendritic cells), elevated PD-L1 expression, and a relatively inflamed TME phenotype[41]. These tumors often demonstrate better responses to ICIs than HPV-negative OSCCs, presenting opportunities for nanoparticle-based delivery of viral antigen-specific immunotherapies and adjuvants to further enhance antitumor immunity. HPV-targeted nanoparticles (e.g., E6/E7 siRNA-loaded lipid nanoparticles) can silence viral oncogenes while immunomodulatory nanoparticles may strengthen endogenous antitumor responses in HPV-positive tumors. For HPV-negative OSCC nanoparticles codelivering stroma-disrupting agents (e.g., TGF-β inhibitors) and ICIs can help mitigate immunosuppression[42,43].

The rich and diverse microbiota of the oral cavity also play a pivotal role in shaping the OSCC microenvironment. Dysbiosis and chronic periodontal inflammation have been implicated in oral carcinogenesis by altering local immune surveillance, modulating inflammatory cytokine networks, and sustaining immunosuppressive cell populations[20]. Certain oral bacterial species can influence macrophage polarization, promote EMT, and facilitate tumor progression[30]. Pathobionts such as Fusobacterium nucleatum and Porphyromonas gingivalis drive chronic inflammation, ECM remodeling, and immune evasion via toll-like receptor (TLR)/nuclear factor kappa B activation, PD-L1 induction, and Treg recruitment. Biofilms formed by these microbes can also physically hinder drug penetration. Consequently, the design of nanotechnology platforms that can modulate microbiota-TME crosstalk through bioresponsive nanoparticles that neutralize microbial metabolites or deliver local immunomodulators represents a promising direction for targeted OSCC therapy[11]. Antimicrobial nanoparticles (e.g., silver or peptide-conjugated nanoparticles) can disrupt pathogenic biofilms while dual-functional nanoparticles can simultaneously deliver antibiotics (e.g., metronidazole) and immunotherapeutics (e.g., anti-PD-1) to counteract microbiota-driven immunosuppression[44,45].

In summary, the OSCC TME is uniquely shaped by lifestyle-associated carcinogens, viral oncogenesis, and oral microbial communities. Future nanotechnology-based strategies should address these site-specific factors to enable more precise and effective reprogramming of the immunosuppressive TME and optimize immunotherapy outcomes in oral cancer.

NANOTECHNOLOGY STRATEGIES FOR TME MODULATION

Nanotechnology has advanced significantly in cancer treatment by improving drug delivery systems, enhancing therapeutic efficacy, and minimizing side effects. In this approach, nanoparticles specifically target tumor cells, addressing critical challenges such as drug resistance and systemic toxicity (Figure 1). Several classes of nanoparticles, including liposomes, dendrimers, and metal nanoparticles, have been designed for targeted delivery, thereby maximizing bioavailability and therapeutic response[46,47]. The enhanced permeability and retention effect enables nanoparticles to preferentially accumulate in tumor tissues, supporting localized treatment delivery[48]. In addition to delivering drugs, nanoparticles can also facilitate diagnostic imaging, allowing for more personalized and precise treatment planning. Some nanoparticle-based techniques utilize light to selectively destroy cancer cells, thereby minimizing damage to surrounding healthy tissues[49]. Nanoparticles can evade efflux pumps and specifically target cancer stem cells, addressing the problem of multidrug resistance. Despite these advancements challenges related to nanoparticle toxicity, biocompatibility, and regulatory approval continue to hinder the widespread clinical adoption of nanotechnology in oncology[50].

Figure 1 Modulation of immune cell function using nanotechnology.

Modulating the TME using nanoparticles offers several advantages for cancer therapy. Such nanoparticles can improve drug delivery, enhance antitumor immune responses, and help create a microenvironment less favorable for tumor growth, ultimately contributing to better treatment outcomes. Nanoparticles can be engineered to release therapeutic agents in response to specific TME conditions, such as low pH or hypoxia, thereby improving drug efficacy while minimizing systemic side effects[51]. Additionally, their ability to penetrate dense ECM structures enables nanoparticles to overcome barriers that often limit the effectiveness of conventional therapies[52]. These strategies include disrupting the ECM or inhibiting CAFs to increase nanoparticle retention and activity within tumors. Metallic nanoparticles can also stimulate immune responses by promoting dendritic cell (DC) maturation and T cell activation, both of which are essential for effective immunotherapy. Moreover, nanoparticles can induce macrophage polarization toward the M1 phenotype, which is associated with enhanced antitumor activity[53].

Metallic nanoparticles may further interact with immune cells to shift responses from immunosuppressive to proinflammatory states, thereby strengthening antitumor immunity[54]. For example, iron-based nanoparticles have been shown to reverse the immunosuppressive microenvironment by modulating lactate production and promoting M1 macrophage polarization[55]. Broad TME modulation can suppress tumor cell survival and growth, reducing the risk of metastasis and recurrence[56]. Although the potential benefits of nanoparticles for TME modulation are promising, challenges such as TME heterogeneity and possible nanomaterial toxicity remain significant barriers that must be addressed to ensure safe and effective clinical application[57].

Design properties of nanoparticles enabling TME modulation

The functionality of nanoparticles in TME modulation is critically determined by three key tunable physicochemical properties: Size; surface characteristics; and stimuli responsiveness. Together, these properties synergistically enable precise targeting and controlled therapeutic delivery in OSCC. Particle size governs biodistribution and penetration dynamics; for example, sub-50 nm nanoparticles can efficiently traverse the dense OSCC stroma but may undergo rapid renal clearance, whereas nanoparticles in the 50-150 nm range optimally exploit the enhanced permeability and retention effect for passive tumor accumulation[53,54]. For instance, 30 nm gold nanoparticles functionalized with anti-CD163 antibodies can leverage the enhanced permeability and retention effect to selectively target M2 TAMs, delivering TLR agonists that reprogram them toward an antitumor M1 phenotype. Conversely, larger nanoparticles (> 150 nm) are more readily phagocytosed by macrophages; for example, M2 peptide-coated 200 nm liposomes encapsulating IL-12 have demonstrated targeted reprogramming of M2 TAMs in hypoxic OSCC niches[55].

Surface engineering further governs cellular interactions and targeting specificity. Cationic nanoparticles (e.g., chitosan-based) can electrostatically bind to anionic TAM membranes but carry a higher risk of opsonization, whereas polyethylene glycol coatings help mitigate immune recognition and prolong circulation time[56]. Ligand functionalization enhances cellular selectivity; for example, mannose-decorated dendrimers exploit mannose receptor overexpression on M2 TAMs to deliver STAT3 siRNA, suppressing IL-10 secretion and alleviating local immunosuppression[57]. Similarly, fibroblast activation protein-α-binding peptides on mesoporous silica nanoparticles enable selective depletion of CAFs through localized doxorubicin release within the OSCC stroma[58]. Biomimetic coatings, such as macrophage-derived membranes, facilitate immune evasion and homologous targeting; for instance, these nanoparticles bind CD44+ OSCC cells and enhance PD-L1 blockade efficiency by three-fold compared to free antibody administration[59].

Stimuli-responsive designs ensure context-specific payload activation. For example, pH-labile bonds (such as hydrazone linkages in hyaluronic acid nanoparticles) disintegrate in the acidic OSCC TME (pH 6.5-6.8), enabling the targeted release of TGF-β inhibitors to suppress CAF activation[60]. Hypoxia-responsive systems, such as azobenzene-linked nanogels, selectively release oxygen-generating perfluorocarbons in hypoxic regions, restoring CD8+ T-cell function[61]. Redox-sensitive thioketal bonds can deliver metronidazole and IL-2 in response to elevated ROS, counteracting microbiota-driven immunosuppression while matrix metalloproteinase-9-cleavable peptides trigger the release of anti-CTLA4 antibodies within protease-rich OSCC stroma[62,63]. Collectively, these structure-function relationships provide a robust framework for engineering precision nanomedicines capable of overcoming OSCC-specific TME barriers.

MODULATION OF IMMUNE CELL FUNCTION USING NANOTECHNOLOGY

TAMs play a central role in the TME with M2 macrophages supporting immunosuppression and tumor progression. Nanotechnology has emerged as a powerful tool to reprogram TAMs from the M2 to the M1 phenotype, thereby enhancing antitumor immunity. Various studies have demonstrated the promise of nanoparticles in this context. For example, a dual nano delivery system integrating R848 and imatinib into Pt^@HP nanocarriers has been shown to selectively target M2-like macrophages and repolarize them toward the M1 phenotype[64]. Similarly, a pH-sensitive, size-switchable nanocluster, SPN-R848, has been developed to remodel the immunosuppressive TME by driving M2-to-M1 macrophage polarization[65]. These approaches not only strengthen the antitumor immune response but also improve the overall effectiveness of immunotherapy.

Tregs and MDSCs are major immunosuppressive cell populations in the TME, and their reprogramming is essential for enhancing tumor-specific immunity. Nanotechnology has been harnessed to target these cells and regulate their immunosuppressive functions. For instance, the antitumor nanovaccine CaGlu nanoparticles, composed of calcium carbonate nanoparticles and β-glucan, has been shown to repolarize tumor-associated macrophages and mitigate the immunosuppressive activity of Tregs[66]. Additionally, multifunctional nanocarriers have been designed to deliver immunogenic cell death stimuli and immune modulatory agents, disrupting immune-escape pathways and counteracting the effects of Tregs and MDSCs[67]. These strategies aim to generate a more immunogenic TME that supports cytotoxic T cell activation and strengthens antitumor immunity.

DCs, as key antigen-presenting cells, play a vital role in initiating and regulating adaptive immune responses. Nanotechnology has been applied to enhance DC activation and maturation, thereby promoting cytotoxic T cell infiltration and antitumor activity. For example, the size-switchable nanocluster SPN-R848 has been engineered to activate DCs in tumor-draining lymph nodes, boosting the generation and activation of cytotoxic T cells. Similarly, nanoparticles have been developed to directly target DCs and deliver immunomodulatory molecules to improve their maturation and antigen-presenting capacity[68]. These innovations not only strengthen DC activation but also facilitate deeper infiltration of cytotoxic T cells into tumors, generating a more robust antitumor response.

Nanocarriers also serve as multifunctional platforms for the targeted delivery of immunomodulatory drugs, enabling effective modulation of immune cells within the TME. These nanocarriers can be tailored to selectively target specific immune cell populations, including TAMs, Tregs, MDSCs, and DCs, and to deliver therapeutic agents in a controlled and sustained manner. Multifunctional nanocarriers can also be engineered to simultaneously deliver combinations of immunogenic cell death stimuli and immune modulatory drugs, producing synergistic effects that further boost antitumor immunity[69]. Such nanocarriers not only increase the efficiency of immunotherapy but also reduce systemic toxicity, making them promising candidates for clinical translation.

Nanoparticles enable precise immune cell modulation through carefully designed physicochemical properties. Size influences biodistribution (sub-50 nm nanoparticles penetrate dense stroma, whereas nanoparticles larger than 100 nm favor phagocytosis), surface charge determines cellular interactions (cationic nanoparticles bind to anionic immune cell membranes), and the payload dictates functional outcomes. Table 2 summarizes key nanoplatforms targeting immunosuppressive cells in OSCC.

Table 2 Summary of nanoparticle designs showing size, surface charge, functional modifications, and their application in targeting key immunosuppressive immune cells such as tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and dendritic cells within the tumor microenvironment.

Nanoparticle type	Size (nm)	Surface charge	Surface modification	Payload	Target immune cell (s)	Key effect	Ref.
Polymeric nanocluster (SPN-R848)	Approximately 100	Slightly positive	pH-responsive polymer shell	TLR7/8 agonist (R848)	TAMs, DCs	Polarizes M2 TAMs to M1, activates DCs	[49]
Lipid-coated CaCO3 NPs (CaGlu)	Approximately 150	Neutral	β-glucan surface	Calcium carbonate + β-glucan	TAMs, Tregs	Repolarizes TAMs, suppresses Tregs	[50]
Biomimetic dendritic cell-like NP	Approximately 120	Near neutral	Decorated with anti CD3/CD28/PD-1	Immunomodulatory antibodies	DCs, T cells	Activates DCs, enhances T cell priming	[56]
Iron oxide NP	Approximately 50	Positive	Mannose ligand	Iron core	TAMs	Promotes M1 polarization via ROS generation	[47]
Liposome-based RNAi NP	Approximately 90	Slightly negative	PEGylation, targeting peptide	siRNA targeting IDO/TGF-β	MDSCs, Tregs	Suppresses immunosuppressive pathways	[51]

TAM: Tumor-associated macrophages; Tregs: Regulatory T cells; MDSCs: Myeloid-derived suppressor cells; TGF-β: Transforming growth factor-beta; IDO: Indoleamine-2,3-dioxygenase; NP: Nanoparticle.

OVERCOMING IMMUNOSUPPRESSION AND HYPOXIA IN TME

Cancer immunotherapy has revolutionized the treatment of many malignancies by harnessing the body’s immune system to identify and eliminate cancer cells. However, its therapeutic efficacy is often limited by factors such as an immunosuppressive TME, abnormal tumor vasculature, and hypoxia. Nanoparticles have emerged as highly promising carriers for delivering ICIs in cancer immunotherapy as they can improve therapeutic performance through multiple complementary mechanisms (Figure 2). One notable advantage is their ability to enhance T cell activation. Nanoparticles can amplify CD8+ T cell responses by codelivering ICIs together with immune-stimulating components, such as adjuvants or tumor-specific antigens. For example, polymeric nanoparticles encapsulating anti-PD-1 antibodies and CpG oligodeoxynucleotides have demonstrated the ability to induce robust T cell-mediated tumor rejection in preclinical models[70].

Figure 2 Heatmap showing specific nanoparticle classes and their principal immunotherapeutic mechanisms in the oral squamous cell carcinoma tumor microenvironment. Rows represent nanoparticle types (e.g., peptide amphiphile, dendritic cell-like, PD-1 membrane-coated, calcium carbonate, metallic nanoparticles) and columns indicate key functions: T cell activation; tumor regression; hypoxia modulation; immunogenic cell death/ferroptosis; CD8+ T cell infiltration; and suppression of immunosuppressive pathways (e.g., IDO/TGF-β). The matrix links each nanoparticle to its main mode of action, illustrating how nanotechnology can target multiple barriers within the oral squamous cell carcinoma tumor microenvironment to enhance immunotherapy efficacy. TGF-β: Transforming growth factor-beta; ICD: Immunogenic cell death; MOF: Metallic organic framework.

Effective T cell activation is a critical step in immunotherapy, enabling the immune system to detect and target malignant cells. Nanoparticles have therefore been engineered to promote T cell activation by delivering immunomodulatory agents directly to T cells or the TME. For instance, calcium signaling plays a fundamental role in T cell activation, and calcium carbonate nanoparticles have been utilized to deliver PMA and calcium ions to T cells, stimulating NFAT and nuclear factor kappa B pathways to boost cytotoxic T cell activity[71]. Biomimetic DC-like nanoparticles have also been developed to stimulate T cells more effectively; these nanoparticles, functionalized with anti-CD3, anti-CD28, and anti-PD-1 antibodies, simultaneously activate T cells and block immune checkpoints, resulting in stronger antitumor responses[72]. Additionally, PD-1-expressing T cell-targeted nanoparticles have been designed to deliver TGF-β inhibitors or TLR7/8 agonists, further enhancing T cell activation and tumor infiltration[73].

Targeted nanoparticle delivery to lymph nodes can also strengthen antigen presentation and T cell priming, thereby improving antitumor immunity[74]. ICIs such as anti-PD-1 and anti-PD-L1 mAbs have shown remarkable clinical potential for various cancers, but their effectiveness is still constrained by limited tumor penetration, systemic toxicity, and the presence of an immunosuppressive TME. Nanoparticles can provide a more focused and efficient delivery platform for ICIs, ensuring local action while minimizing off-target side effects. For example, peptide amphiphile nanoparticles have been engineered to release anti-PD-1/PD-L1 inhibitors specifically within the TME, facilitating greater infiltration of cytotoxic T cells and achieving improved therapeutic outcomes[75,76]. Nanoparticles can also be designed for the simultaneous delivery of multiple immunomodulatory agents. For instance, nanoparticles have been developed to codeliver anti-PD-1 and anti-OX40 antibodies, resulting in enhanced T cell activation and greater tumor regression compared with free antibodies alone[77]. Additionally, nanoparticles coated with PD-1 cellular membranes have been shown to disrupt the PD-1/PD-L1 axis, triggering potent antitumor immune responses[78].

Beyond immune activation nanoparticles have also been employed to normalize the aberrant vasculature typical of tumors. Hybrid nanoparticle systems coloaded with anti-VEGF siRNA and ICIs have demonstrated the ability to remodel tumor vasculature, improving perfusion and facilitating T cell access to the TME. Such vascular normalization not only enhances immune cell infiltration but also alleviates interstitial pressure and promotes better delivery of therapeutic agents[79]. Abnormal tumor vasculature is a hallmark of many cancers and contributes to hypoxia, immune evasion, and inefficient drug distribution. By normalizing this vasculature, perfusion can be increased, hypoxia reduced, and immune cell infiltration improved. Peptide amphiphile nanoparticles carrying antiangiogenic peptides, for example, have been shown to normalize tumor vasculature, resulting in improved perfusion and reduced hypoxia[80]. Furthermore, nanoparticles that deliver antiangiogenic agents such as bevacizumab have been used to normalize tumor blood vessels and enhance the delivery of both chemotherapeutic agents and ICIs[81]. Improved vascular normalization not only facilitates drug penetration but also supports deeper infiltration of cytotoxic T cells, amplifying antitumor immune effects.

A major challenge for cancer immunotherapy is the immunosuppressive nature of hypoxic TME. To address this nanoparticles have been developed to deliver oxygen-generating compounds or hypoxia-responsive therapeutics[82]. Oxygen-releasing nanoparticles are specifically designed to mitigate the hypoxic conditions that characterize solid tumors such as OSCC. These nanoparticles may encapsulate oxygen-rich compounds like PFCs or incorporate catalase-like enzymes that convert endogenous hydrogen peroxide into oxygen within the TME. By locally generating or transporting oxygen, these nanoparticles increase the partial pressure of oxygen in hypoxic tumor regions, helping to normalize pathways that support immune suppression. Reoxygenation improves the function of cytotoxic T lymphocytes and natural killer cells, enhances the performance of ICIs, and makes tumors more susceptible to other immunotherapies[83].

For instance, oxygen-generating nanoparticles codelivering anti-PD-L1 have been shown to restore T cell function and promote tumor clearance under hypoxic conditions. Alleviating hypoxia has also been linked to increased MHC expression, further enabling effective T cell recognition and tumor cell killing. Some nanoparticles have been designed to counteract hypoxia by delivering oxygen or by inhibiting HIF. For example, nanoscale metallic organic frameworks have been engineered to penetrate hypoxic tumor areas and enhance photodynamic therapy (PDT). These metallic organic frameworks, composed of iron-oxo clusters and porphyrin ligands, can sensitize PDT under both normoxic and hypoxic conditions, leading to significant tumor regression and stronger antitumor immunity[84]. Additionally, nanoparticles have been used for the delivery of RNA interference targeting lactate dehydrogenase A, a key enzyme involved in lactate production and tumor acidification. By suppressing lactate formation and counteracting tumor acidity, these nanoparticles restore T cell function and further boost the effectiveness of ICIs[62].

CHALLENGES AND FUTURE PERSPECTIVES

While nanoparticles hold great promise for advancing cancer immunotherapy, several challenges must still be addressed. These include the complex design requirements of nanoparticle systems, their potential toxicity, and the need for rigorous clinical validation. In addition, the immunosuppressive TME and the inherent heterogeneity of tumors present significant barriers to effective nanoparticle-based treatment. The clinical implementation of nanoparticle-mediated TME modulation faces multiple hurdles, including concerns about immunogenicity, off-target effects, and broader safety considerations. A key challenge is the host immune response, particularly the recognition and clearance of nanoparticles by macrophages within the mononuclear phagocyte system, which can reduce therapeutic efficacy and increase systemic toxicity[85].

Ensuring the molecular-level safety of nanoparticles also demands extensive research into their interactions with biomolecules to avoid unintended biological effects[86]. Beyond scientific challenges regulatory and standardization issues remain substantial obstacles. The evolving and complex regulatory landscape requires harmonized international standards and consistent protocols for evaluating the efficacy and safety of nanomedicine[87]. Moreover, standardization of nanoparticle synthesis and characterization must be prioritized with particular attention to achieving batch-to-batch reproducibility and scalability, goals that can be more readily met through early coordination with regulatory agencies[88].

Despite these challenges there are promising opportunities for the future. Personalized nanomedicine, which tailors nanoparticle design to individual patient profiles and the specific features of their TME, offers the potential for improved therapeutic outcomes. Furthermore, combining nanoparticles with other treatment modalities may enhance efficacy and help overcome therapeutic resistance[90-94]. The development of advanced biomaterials that are both biocompatible and efficient in drug delivery further strengthens the potential of nanoparticle-based therapies. Although significant barriers to clinical translation remain, these emerging strategies provide a compelling outlook for the safe and effective use of nanoparticles to modulate the TME in cancer therapy[89-92].

Clinical translation of nanotechnology in OSCC

While nanotechnology-based therapies have demonstrated encouraging outcomes in preclinical studies, their translation into clinical practice for OSCC remains in its early stages. Several clinical trials are currently underway investigating nanoparticle formulations in head and neck squamous cell carcinoma, of which OSCC constitutes a major subgroup.

In a phase I/II study[93] intratumoral administration of hafnium oxide nanoparticles combined with radiotherapy achieved complete tumor regression in 17% of patients with advanced head and neck cancer, a notable improvement compared with non-injected control sites, by enhancing radiotherapy effects without additional toxicity. This result has led to an ongoing phase III trial focused specifically on the oral cavity[94]. For patients with recurrent metastatic disease, liposomal cisplatin has demonstrated an 11% overall response rate and a median progression-free survival of 4.2 months in platinum-resistant cases, attributed to improved tumor drug accumulation[95]. Similarly, nanoparticle-camptothecin in combination with chemoradiation achieved an 89% 2-year locoregional control rate while significantly reducing the severity of mucositis[96]. Early-phase investigations of immunoliposomal anti-epidermal growth factor receptor (EGFR) (anti-EGFR ILs-Dox) have reported partial responses in 20% of patients with refractory head and neck squamous cell carcinoma by delivering doxorubicin directly to EGFR-expressing tumor cells[97].

Recent developments include intratumoral delivery of NanoPac^® (nanoparticulate paclitaxel)[98] for localized oral lesions, mRNA-nanoparticle vaccines targeting HPV E6/E7 oncoproteins in virus-driven cancers[99], and photothermal gold nanoparticle therapy for early-stage lesions[100]. Despite this progress translation to routine clinical practice faces several hurdles: Variable tumor permeability can limit consistent nanoparticle delivery; manufacturing challenges persist regarding the reproducibility of complex nanocarriers; and regulatory frameworks have yet to fully adapt to evaluate multifunctional nanoparticle platforms.

Nevertheless, these clinical investigations represent substantive advances toward integrating nanotechnology into standard OSCC care although broader adoption will require overcoming technical, manufacturing, and regulatory barriers.

Clinical trial advancements

A number of ongoing clinical trials are investigating nanoliposomal immunotherapies and TME-modulating nanoparticles in head and neck cancers, including OSCC. The phase III PIVOT-09 study[94] is evaluating hafnium oxide nanoparticles activated by radiotherapy for locally advanced OSCC, building on earlier phase I/II results that demonstrated a complete response rate of approximately 16.7% without additional toxicity[93]. For patients with metastatic or recurrent disease, a phase II trial of liposomal cisplatin[95] reported an overall response rate of 11% in platinum-resistant cohorts with a median progression-free survival of 4.2 months[94]. In parallel, the BNT113 mRNA nanoparticle vaccine, developed to target HPV16-positive tumors, has shown an objective response rate of about 50% among PD-L1–positive head and neck SCC cases when combined with pembrolizumab; reported grade 3 adverse effects were primarily limited to fatigue (15%) and rash (10%)[101]. Moreover, a phase I study[97] of an immunoliposomal anti-EGFR agent demonstrated partial responses in roughly 20% of patients who were heavily pretreated. Infusion-related reactions were generally mild (grade 1-2) and occurring in about 40% of participants. Collectively, these trials highlight the translational potential of nanotechnology-based strategies to counteract immunosuppression in OSCC while maintaining an acceptable safety profile.

Current research is focused on optimizing nanoparticle design, improving targeting specificity, and developing combination approaches to overcome existing limitations. Future directions include the advancement of stimuli-responsive nanoparticles capable of sensing and adapting to the dynamic TME as well as the integration of nanotechnology with other immunotherapeutic strategies, such as CAR-T cell therapy and cancer vaccines. The development of theranostic nanoparticles, which combine diagnostic and therapeutic functions, represents another promising area of investigation.

CONCLUSION

Although immunotherapy has demonstrated considerable promise, its efficacy is often undermined by the highly immunosuppressive TME. Nanotechnology has emerged as a potential strategy to remodel the TME, strengthen antitumor immune responses, and improve the outcomes of immunotherapy in OSCC. The oral cancer TME is characterized by multiple immunosuppressive elements, including TAMs, Tregs, MDSCs, and hypoxia, all of which inhibit T cell infiltration and activation, leading to suboptimal responses to immunotherapy. Additionally, the typically low expression of PD-L1 in OSCC further constrains the effectiveness of ICIs.

To address these challenges nanoparticles have been engineered for precise drug delivery, immune modulation, and enhanced therapeutic accumulation within the TME. Their structural versatility and ability to carry multiple functional payloads make them well-suited for TME modulation. One promising approach targets TAMs, which sustain immunosuppression within the TME. Nanoparticles can be designed to reprogram TAMs toward the proinflammatory M1 phenotype, thereby promoting robust antitumor immunity. For example, macrophage membrane-coated nanoparticles have been shown to inhibit tumor growth effectively while stimulating immune responses.

Another strategy involves the use of nanoparticles to induce immunogenic cell death through PDT. When photosensitizers are encapsulated within nanoparticles, they can generate ROS upon activation, triggering immunogenic cell death, releasing tumor antigens, and subsequently activating DCs and cytotoxic T cells.

Combining nanoparticles with ICIs also holds significant promise. Tumor membrane-encapsulated nanoparticles delivering PD-1 siRNA have been shown to suppress PD-1 expression, enhance T cell activation, and inhibit OSCC progression in preclinical models. In addition, stimuli-responsive nanoparticles that release therapeutic agents in response to specific triggers, such as pH, light, or temperature, have been developed to achieve localized delivery while minimizing systemic toxicity. Integrative strategies combining nanoparticles with chemotherapy, radiotherapy, or PDT have likewise shown potential for converting immune-resistant tumors into immunotherapy-responsive tumors by promoting greater immune cell infiltration and activity.

While preclinical findings are encouraging, the clinical translation of nanoparticle-based approaches continues to face challenges. Ensuring safety, demonstrating sustained efficacy, and achieving scalable production remain essential, especially given the inherent heterogeneity of the TME. To maximize therapeutic success personalized nanomedicine approaches tailored to individual tumor profiles may ultimately be required. Nanotechnology represents a powerful tool for modulating the immunosuppressive TME and enhancing the effectiveness of immunotherapy in oral cancer; however, further research and clinical validation will be critical to achieving its full translational potential.