Targeted immunotherapies and nanomedicines for ovarian cancer: the way forward

Abstract

Ovarian cancer (OC) is the leading cause of death among gynecological cancers, with high mortality due to late diagnosis. Immunotherapy and nanomedicine show potential in targeting cancer cells and inducing immunogenic cell death. However, challenges like poor biodegradability and untargeted immune activation persist. Emerging solutions, including enhanced nanoparticles and personalized medicine, aim to improve efficacy while minimizing side effects by tailoring treatments to individual profiles and disease stages.

Introduction

Ovarian cancer (OC) is the second most common gynecological malignancy, following cervical cancer and uterine tumours¹. Many women delay cancer screening due to the absence of obvious symptoms, such as abdominal discomfort². Consequently, numerous OC patients are diagnosed at later stages, leading to poorer prognoses. The 5-year cause-specific survival rates for Stage I and Stage II OC are 90% and 70%, respectively, while those for Stage III and Stage IV are 40% and 20%³. Post-surgery, women with OC typically undergo a combination of chemotherapy and radiotherapy, although the adverse effects of these treatments must not be overlooked⁴.

Immunotherapy offers a lower recurrence rate and greater specificity compared to conventional therapies⁵. Its primary objective is to activate the host immune system to trigger either passive or active immune responses against malignant tumours, representing a significant advancement in OC treatment⁶. Previous studies have confirmed that atilizumab works well in combination with bevacizumab and non-platinum chemotherapy, in treating recurrent OC, thus providing a new therapeutic option⁷. Furthermore, atilizumab-based combination therapy has demonstrated potential in improving overall survival (OS) and progression-free survival (PFS) in recurrent OC treatment⁸. However, challenges such as the deregulation of cellular metabolism and immune evasion remain prevalent in immunotherapy, indicating that a multidisciplinary approach is essential for further progress.

Nanomedicine has become an emerging science in cancer treatment over the past years, especially in detection of the early cancer cells⁹. Magnetic nanoparticles (MNPs) in Magnetic Resonance Imaging (MRI) boast excellent image contrast because of their special magnetic behavior, thus emerging as the next-generation material require in MRI¹⁰. Several applications of MNPs are also being investigated in the field of thermotherapy to help in physical ablation of tumour tissue¹¹. More recently a new interdisciplinary area is gaining momentum as totting up the merits of nanomedicine and immunotherapy. Such synergy has been shown to enhance the performance of the two modalities in increasing patient outcomes by enhancing the effectiveness of each and reducing the shortcomings of each modality. Nanocarriers can be tailored to allow a high degree of control infecting when and where immune modulation, predetermined by immunotherapy, to occur to minimize immune side effects and enhance anti-tumour immunity. In addition, it is also possible to enhance the therapeutic capabilities of nanomedicine by the activation or exertion of immune cells or immunosuppressive cells. This combined approach also bears potential in solving the typical clinical problem, namely of low tumour accumulation of nanocarriers. This would increase the efficiency of immunotherapy by using lens nanoparticles to deliver drugs to additional types of cells, eventually elevating the success of cancer therapy.

Through this work, the researcher will set out to offer a review of immunotherapy in OC and how MNPs are used to diagnose as well as treat the disease. Having outlined recent developments in immunotherapy and MNPs we will discuss later their possible uses in OC. Lastly, the potential and obstacles of integrating immunotherapy and MNPs will also be discussed as well as how nanotechnology can be used as a tool in diagnosing and treating OC.

Current status in the treatment of OC

The early symptoms of OC are not readily apparent, and by the time a diagnosis is made, the disease is often already in an advanced stage¹². This underscores the critical importance of early diagnosis in improving patient survival rates. Currently, ultrasonography is the most widely employed method for early diagnosis in clinical practice¹³. However, due to the unique anatomical location of the ovary, ultrasonography may fail to detect small OC lesions in the early stages of the disease¹⁴. The primary sites of metastasis for OC are intra-abdominal implants, in addition to lymphatic and haematogenous metastasis. The assessment of metastasis risk is facilitated by imaging modalities such as CT and MRI, though these are not without limitations¹⁵. CT, while capable of delineating intra-abdominal structures and tumour characteristics, may lack the precision to accurately detect small metastatic foci, particularly those that are minimally implanted in the peritoneum, due to its inherent resolution limitations¹⁶. Although MRI has the advantage of enhanced soft-tissue resolution, it too faces challenges in detecting very early metastatic foci, such as minute tumour cells that have only just begun to be implanted in the intra-abdominal cavity. Furthermore, MRI is susceptible to motion artefacts, which can compromise image quality and, consequently, the ability to accurately identify metastatic foci¹⁷. In light of these limitations, there is an evident need for the development of a comprehensive and accurate evaluation system that can facilitate early diagnosis of OC and prediction of metastasis in clinical practice.

In clinical practice, the primary treatment modality for patients diagnosed with OC is surgery¹⁸. The surgical procedure is accompanied by a number of challenges, including the presence of tight adhesions between the tumour and the surrounding tissues¹⁸. OC has a high potential for invasion of surrounding organs, including the bowel, bladder, and others¹⁹. The process of separating adhesions during surgery carries a risk of damage to these organs. Consequently, the combination of surgery with chemotherapy and targeted therapy is frequently employed in clinical practice for patients with advanced OC. However, in addition to killing tumour cells, chemotherapy medications also kill healthy cells. The great degree of specificity of targeted therapy, which enables it to act specifically on tumour cells, is a major benefit. Targeted therapy lowers the risk of side effects when compared to chemotherapy. Targeted therapy can have certain drawbacks, though. As treatment is prolonged, tumour cells may find other ways to evade the targeted medications’ mechanism of action, which would reduce their effectiveness²⁰. Thus, it is imperative to investigate novel therapeutic approaches.

New strategy for OC treatment - immunotherapy

OC treatment has been hindered by tumour heterogeneity and the complex immune microenvironment. As a result, innovative immunotherapies have become central to overcoming these challenges. Recently, targeted immune cell-based therapies have made significant progress. This discussion focuses on three key immune cell types: Chimeric antigen receptor T-cell immunotherapy (CAR-T) cells, a genetically engineered approach targeting cancer cells; tumour-associated macrophages (TAMs); and natural killer (NK) cells, both of which are crucial targets in OC immunotherapy. TAMs regulate the tumour microenvironment, while NK cells provide innate anti-tumour activity. The following sections will explore the biomarkers, functions, and therapeutic potential of these immune cells in OC treatment (Table 1).

Table 1.

Application of CAR-T therapy, TAMs, and NK cells in ovarian cancer treatment

Types of immunotherapy	Biomarkers	Efficacy evaluation	Reference
CAR-T Cell Therapy (Tumour cell surface)	MSLN	Targeted destruction of tumour cells to inhibit tumour growth	24
	PTK7	In vitro potent killing of PTK7-positive ovarian cancer cells In vivo tumour clearance	24
	TM4SF1	Specifically kills TM4SF1-positive tumour cells, inhibiting tumour growth derived from SKOV3 cells.	25
TAMs (Tumour microenvironment)	CD206	Inhibit M2-type polarisation, promote conversion to M1-type, and reduce peritoneal metastasis.	31
NK cells (NK cell surface)	NKG2D	Activate NK cells to enhance cytotoxic activity; Combine with anti-HER2 antibodies to enhance killing via ADCC.	43
	HER2	Specifically recognises OC cell antigens, enhancing targeted killing efficiency	42

CAR-T cells

CAR-T is an innovative treatment in which T-cells are engineered to specifically target tumour-associated antigens (TAA) or tumour-specific antigens (TSA) overexpressed on cancer cells(Fig. 1)²¹. Unlike conventional immunotherapies, CAR-T cell therapy induces tumour cell lysis independently of the tumour-associated immune response, thereby exerting efficient and specific tumour cytotoxicity²². In the context of OC, several potential antigens have been identified as targets for CAR-T cell therapy due to their high expression levels and specificity²³. The most promising targets include mucin 16 (MUC16), mesothelin (MSLN), folate receptor 1 (FOLR1), and tumour-associated glycoprotein 72 (TAG72), with encouraging responses observed both in vitro and in vivo²³.

Fig. 1. CAR-T therapy as an immunotherapy for the treatment of OC.

Steps 1 to 6 represent each stage of the CAR-T therapy.

Kim et al. confirmed that MSLN targeting CAR-T cells significantly reduced the growth of OC cells, indicating that CAR-T therapy may be used as an immunotherapy to treat OC²⁴. Further studies have developed CAR-T therapies targeting protein tyrosine kinase 7 (PTK7) through the TREM1/DAP12 signaling pathway²⁴. This approach demonstrated potent cytotoxicity against PTK7-positive OC cells in vitro and successfully eradicated tumours in animal models²⁴. Another promising advancement is a third-generation CAR-T therapy targeting transmembrane 4 L family member 1 (TM4SF1), which has shown specific cytotoxicity against TM4SF1-positive tumour cells in vitro and inhibited SKOV3-derived tumour growth in vivo²⁵. However, OC is a highly heterogeneous tumour with variability in the expression of surface antigens, making the selection of appropriate antigens for CAR-T cells a critical challenge²⁶.

Tumour-associated macrophages

Macrophages are a crucial component of the innate immune system in humans. Within the TME, these cells are referred to as TAMs²⁷. TAMs can arise from two sources: circulating monocytes that are recruited to the tumour site and subsequently mature, or resident tissue macrophages that undergo differentiation²⁸. These macrophages play critical roles in all stages of OC progression, including cancer proliferation, dissemination, and recurrence(Fig. 2)²⁹.

Fig. 2. TAM promotes ovarian cancer progression in a number of ways.

TAMs A promote angiogenesis in tumor cells, thereby promoting proliferation; B promote the EMT process of tumor cells, thereby facilitating metastasis; and C promote tumor recurrence.

TAMs in the context of OC frequently exhibit M2 polarization, which is strongly associated with immunosuppression and tumour promotion³⁰. M2-type TAMs release anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which suppress immune responses triggered by cancer cells³¹. In addition to immune suppression, these macrophages significantly contribute to angiogenesis, tissue remodeling, and the creation of an immunosuppressive TME³². Research by Mistarz et al. indicates that the proportion of M2-type TAMs in the ascites of OC patients correlates positively with tumour stage, reaching as high as 62% in stage IV patients³³. Regarding therapeutic strategy exploration, advances have been made in TAM reprogramming approaches for OC. For instance, in an OC-bearing mouse model, intervention with the colony-stimulating factor 1 receptor inhibitor pexidartinib reduced M2-type TAM proportion within the tumour microenvironment by 40% compared to controls, concurrently exhibiting a marked increase in pro-inflammatory M1 macrophages, ultimately effectively inhibiting the formation and growth of peritoneal metastatic foci in OC³⁴. These OC-specific findings further underscore the therapeutic potential of targeting TAMs in OC treatment. The aforementioned findings not only clarify the pivotal regulatory role of M2-type TAMs in OC progression but also provide crucial theoretical underpinnings for developing novel targeted therapeutic strategies. This suggests that immunomodulatory therapies targeting M2-type TAMs may represent a promising avenue for improving patient outcomes in OC.

NK cells

NK cells are immune cells within the human immune system that can recognize and eliminate abnormal cells, including tumour cells, without prior sensitization³⁵. In vitro, NK cells can be activated and expanded through cytokine stimulation³⁶. Kaminski’s study demonstrated that cytokines, such as interleukin-2 (IL-2) and interleukin-15 (IL-15), stimulate the proliferation and activation of NK cells³⁷. These activated NK cells can be cultured in large quantities in vitro and subsequently infused back into OC patients to increase the population of NK cells with cytotoxic activity in the body³⁸. Additionally, NK cells can be genetically modified to express molecules that enhance their activity³⁹. Yang et al. suggests that NK cells can be modified to express chimeric antigen receptors (CARs), enabling them to specifically target OC cells by recognizing antigens on their surface, such as mesothelin and folate receptor α, similar to CAR-T cells⁴⁰.

Certain monoclonal antibodies can be used as targeted agents to enhance the cytotoxic effects of NK cells against OC⁴¹. For example, anti-HER2 (Human Epidermal Growth Factor Receptor 2) antibodies bind to the HER2 antigen on the surface of OC cells, enabling NK cells to recognize the antibody-antigen complex via the Fc receptor on their surface, thereby triggering NK cell cytotoxicity⁴². This antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism significantly enhances NK cell-mediated destruction of OC cells⁴³. Immune checkpoint inhibitors can also be used in combination with NK cell therapy. The OC tumour microenvironment contains several immunosuppressive factors, such as the programmed death receptor-1 (PD-1) and programmed cell death ligand 1 (PD-L1) pathway⁴⁴. Immune checkpoint inhibitors can block the PD-1/PD-L1 pathway, alleviating NK cells from immunosuppression and allowing them to better execute their anti-tumour function⁴⁵.

Aligned with precision medicine, personalized NK cell therapy can be tailored based on an individual patient’s tumour antigenic characteristics, immune status, and other factors⁴⁶. Furthermore, extensive research into the mechanisms of combination therapy will be necessary to optimize the combination and sequencing of therapies, such as NK cell therapy combined with surgery, chemotherapy, radiotherapy, and other immunotherapy methods, in order to achieve synergistic therapeutic effects and improve treatment outcomes for OC.

Magnetic nano-driven nanomedicine in OC

MNPs typically range in size from 1 to 1000 nanometers⁴⁷. At medium sizes, (degree to less than about 20 nanometers) they are superparamagnetic, which can be moved and repositioned flexibly under external magnetic fields⁴⁸. This aspect allows accurate targeting of MNPs in the body allowing targeted delivery of MNPs to specific tumour tissues in biomedical applications⁴⁹. MNPs have a proportional shape geometries and the size uniformity is a significant feature to ensure stable geometries of a material⁵⁰. It is said that as the size distributions of MNPs are uniform the accuracy of drug releasing and drug loading in the drug delivery systems is enhanced⁵¹. Also, their large specific surface area gives them numerous active sites on which to chelate and load different materials. MNPs have demonstrated that properties in drug delivery drug molecules can be adsorbed to the surface to control their release rates by adjusting the surface properties⁵². By means of chemical modifications biomolecules, e.g. antibodies and proteins can be conjugated, which increases their biocompatibility and targeting potential⁵². The work of Natalia showed that MNPs being conjugated with antibodies identifying antigens on tumour cell surfaces displays particular binding and recognition of tumour cells⁵³. Moreover, MNPs are useful in delivering targeted drug injections because they can deliver drugs to pathological sites when the magnetically-directed planners use a magnetic field. They are also used in therapy of hyperthermia where local heat can be generated in diseased areas using the magneto-thermal effect⁵⁴. MNPs can be made biocompatible by coating them with polyethylene glycol (PEG), reducing the immune reaction, and causing the nanoparticles to operate safely within the body⁵⁵. Direction and strength of magnetic field can be used to regulate MNP motion in vitro. They in vivo use magnetic direction to maneuver through blood vessels and the tissues that they target⁵⁶.

To address the off-target effects and safety concerns associated with prolonged use of MNPs, multiple multidimensional strategies have been developed. One approach involves encapsulating MNPs within homologous OC cell membranes or erythrocyte membranes. This utilises ‘self-recognition signals’ on the membrane surface (such as CD47) to inhibit macrophage phagocytosis, while simultaneously enhancing tumour enrichment through homologous targeting⁵⁷. This strategy exploits intrinsic recognition mechanisms during intraperitoneal administration, aligning with OC’s peritoneal metastatic characteristics⁵⁷. Furthermore, modifications with natural polysaccharides like hyaluronic acid (HA) and chitosan enable HA to bind to the CD44 receptor overexpressed on OC cell surfaces, thereby enhancing targeted delivery while reducing immune activation⁵⁸. Studies confirm a 40% reduction in IL-6 release compared to unmodified MNPs⁵⁸. Research by Peng et al. demonstrates that encapsulating or grafting immunosuppressive molecules (such as CD47 mimetic peptides) within phospholipid bilayers reduces macrophage phagocytosis by 58%, thereby minimising systemic inflammatory responses⁵⁹. Daneshpour et al. further demonstrated that degradable MNPs composed of poly(lactic-co-glycolic acid) (PLGA) or iron-based cores progressively degrade in vivo into small-molecule metabolites⁶⁰. Compared to conventional MNPs, these degradable nanoparticles exhibited a 72% reduction in hepatic accumulation over four weeks without significant metabolic toxicity⁶¹. Regarding systemic toxicity control, precise regulation of particle size and surface charge substantially reduced deposition in non-target organs such as the spleen and kidneys⁶². Long-term animal studies confirmed no hepatic or renal dysfunction or tissue damage following eight weeks of continuous administration⁶³. Collectively, these safety optimisation strategies significantly enhance the application potential of MNPs in biomedical fields (Fig. 3).

Fig. 3.

MNPs in the diagnosis and treatment of ovarian cancer.

Recent advancements in the use of MNPs for OC treatment are promising. A 2024 study published in the Journal of Nanobiotechnology developed folate-modified Fe₃O₄ MNPs, which exhibited exceptional targeted accumulation at tumour sites in an OC mouse model. The fluorescence intensity ratio between tumour and normal tissue was found to be 8.3⁶⁴. When combined with the chemotherapeutic agent cisplatin, the MNPs showed a 50% increase in tumour volume reduction compared to cisplatin monotherapy. Rakesh et al. developed a core-shell structured magnetoelectric composite nanoparticle (CoFe₂O₄@BaTiO₃) that achieves highly specific delivery of paclitaxel to ovarian cancer cells (SKOV-3) through external magnetic field-induced nanoelectroporation. In vitro experiments demonstrated the system’s capacity to completely eradicate tumour cells within 24 h while causing no significant damage to normal cells. This exhibits excellent drug delivery efficiency and biocompatibility, offering a potential novel strategy for cancer treatment⁶⁵. These findings, along with the long-term safety optimization strategies mentioned earlier, further support the clinical potential of MNPs in OC therapy. Simultaneously, surface engineering of MNPs has enabled precise targeting of OC-associated biomarkers. Researchers have developed targeted surface modification strategies using CA125 and MSLN as tumour markers. For instance, after modification with anti-CA125 monoclonal antibodies, MNP uptake in CA125-positive OC cells was three times higher than in cells exposed to unmodified particles⁶⁶. Furthermore, conjugating mesothelin aptamers to the MNPs surface resulted in a 2.8-fold increase in tumour-targeting efficiency in a peritoneal metastasis model of OC, which exhibited high mesothelin expression⁶⁷. This enhancement in targeting efficiency lays the groundwork for potential combination immunotherapies, improving therapeutic outcomes in OC.

Magnetic nano-based crossover therapy for treating OC

Tumour ablation techniques

Tumour ablation techniques have emerged as a transformative advancement in cancer treatment, providing effective therapeutic options for patients who are either unable to tolerate conventional surgery or are unsuitable for surgical resection due to tumour location or multiple underlying systemic conditions⁶⁸. Among these techniques, nanoknife technology, based on irreversible electroporation (IRE), offers particularly significant advantages. It enhances local therapeutic efficacy while substantially reducing treatment-related side effects⁶⁹. This technology achieves breakthroughs by precisely locating lesions using optimized imaging guidance systems, combined with multi-modal synergistic anti-tumour strategies. The core mechanism involves implanting customized probes into tumour tissue to deliver high-voltage electrical pulses⁷⁰, inducing irreversible electroporation at the nanoscale to disrupt tumour cell membrane integrity⁷¹. Damaged tumour cells then undergo programmed cell death (apoptosis)⁷², and the immune system, particularly phagocytes, clears apoptotic debris via phagocytosis⁷³. This process ultimately replaces the treated area with healthy tissue, achieving complete eradication of cancer cells. Importantly, this approach causes minimal damage to adjacent healthy tissue, offering unique therapeutic value for cancers that are inoperable or have metastasized.

It is important to note that IRE not only directly destroys tumour cells but also activates the body’s anti-tumour immune response. This is achieved through the promotion of dendritic cell maturation and an increase in the proportion of infiltrating CD8⁺ T cells within the TME, which enhances the potential for synergistic effects with immunotherapy⁷⁴. In clinical practice, for OC patients with concurrent gallbladder metastases and hepatic hilum lymph node involvement, a combined approach of “IRE ablation of tumour margins + blunt dissection” is often used for lesions at the gallbladder-liver junction. This strategy achieves complete lesion clearance while maximizing the preservation of functional hepatic tissue⁷⁵. Data from the clinical trial indicate that this approach reduces the risk of hepatic failure by 60%. For diaphragmatic pedicle metastases, a sequential treatment strategy combining “IRE ablation of tumour core + local injection of PD-1/TGF-β bispecific nanogel (NanoImmune®)” is employed, synergistically enhancing therapeutic efficacy by inactivating tumour cells and remodeling the tumour immune microenvironment⁷⁶.

Drug delivery

The field of targeted drug delivery has advanced rapidly in recent years, emerging as one of the most promising strategies in cancer treatment⁷⁷. This approach enhances therapeutic efficacy while minimizing the side effects typically associated with conventional treatment methods. MNPs have attracted significant attention as effective drug delivery platforms due to their versatility and precision in targeting tumour sites (Fig. 4).

Fig. 4. MNPs for drug delivery in targeting ovarian cancer.

A MNPs for encapsulated drugs; B external stimuli; C passive targeting; D drug release.

Nanoparticles of iron oxide (Fe3O4) that may be functionalised with PEG or linked to targeting ligands including folic acid or antibodies are a promising innovation in targeted drug delivery. The transport of these nanoparticles towards the tumour site is facilitated by the application of outside magnetic field, whereas the low acidity of the TME is used to release the encapsulated drug (Fig.4). This has been demonstrated in preclinical tumour models of breast and liver cancer to raise the drug concentration in the tumour by 3–5 fold reduction of cardiotoxicity⁷⁸. Initial phase clinical trials have shown that the approach offers better inhibition of solid tumours than conventional chemotherapy, and is thus a promising alternative to conventional treatment. Among them, the application of MNPs against paclitaxel and having temperature-reactive polymers like poly- N-isopropylacrylamide is remarkable. Once placed under alternating magnetic field, the resulting nanoparticles emulate heat (42–45 °C) inciting tumour cell death. The heating localization induces the release of the drug into a rapid manner as well. This combined therapy of localized heating and localized drug delivery, in a mouse model of glioblastoma, shrunk tumour volume by 70 percent and minimized the occurrence of neurotoxicity⁷⁹. Other more recent advances involve the application of mesoporous iron oxide nanoparticle which can adsorb cisplatin but having epidermal growth factor receptor (EGFR)-antibody designated onto its surface. The design makes it possible to dual target with magnetic and antibodymediated targeting such that there is drastic lowering of toxicity of cisplatin towards kidneys and hearing. This increased tumour inhibition by 40% and reduction of systemic drug diffusion by 50% in the case of head and neck cancer models which highlights the strength of targeted drug delivery in reducing off-target effects⁸⁰. The other promising approach is co-loading of MNPs with doxorubicin and small interfering RNA (siRNA), i.e., siRNA against anti-apoptotic gene B-cell lymphoma-2 (Bcl-2)⁸¹. Such a mixture can be used to simultaneously administer both chemotherapeutic and gene-based therapies under the control of a magnetic field. Combination therapy with these therapies greatly boosts tumour cell apoptosis and in models of pancreatic cancer, the combination therapy increased survival by two-fold⁸². A specific example of clinical application is NanoTherm® therapy, which uses aminosilane-coated iron oxide nanoparticles (10–15 nm in size)⁸³. Upon injection into the tumour, these nanoparticles are activated by an alternating magnetic field, producing heat while simultaneously releasing chemotherapeutic agents like 5-fluorouracil. NanoTherm® therapy has received European CE marking for the clinical treatment of recurrent glioblastoma and prostate cancer, marking a significant step toward the integration of magnetic nanoparticle-based treatments in oncology.

In the domain of OC treatment, magnetic nanoparticle drug delivery systems have demonstrated considerable promise. Research indicates that for common chemotherapy drugs used against OC (e.g. paclitaxel and cisplatin), loading them onto MNPs and then modifying them for OC-specific targeting (e.g. CA125 antibody modification) results in a 4–6 times increased concentration of the drug at the tumour site in the abdominal cavity of mouse models compared to traditional delivery methods, while significantly reducing toxicity to healthy reproductive tissues such as the ovaries and uterus⁸⁴. Furthermore, given that OC frequently metastasises to the abdominal cavity, magnetic nanoparticle drug delivery systems have the potential to administer drugs via intraperitoneal injection, guided by an external magnetic field to more accurately target metastatic sites within the abdominal cavity. This approach would increase drug concentration at these metastases and provide a new method of treating OC abdominal metastasis.

MNPs are revolutionizing chemotherapy by transforming it from a broad, indiscriminate approach to a more precise, personalized form of treatment. Through magnetic targeting, stimuli-responsive drug release, and multimodal synergistic therapies, MNPs are positioning themselves as powerful tools for personalized cancer therapy. While there are still technical and translational challenges to overcome, the potential of these nanoparticles for advancing precision medicine is becoming increasingly apparent, offering hope for more effective and targeted cancer treatments in the future.

Thermotherapy treatment

Among the innovative therapeutic strategies being explored, magnetothermal processes stand out. The magneto-thermal effect is inherent to certain MNPs and, coupled with their high surface area-to-volume ratio, facilitates efficient heat transfer to the surrounding tissues⁸⁵. This property forms the basis of a novel cancer treatment modality, thermotherapy. Cancer cells are particularly susceptible to heat due to the acidic microenvironment within the tumour, which reduces their heat resistance⁸⁶. Additionally, the tumour’s chaotic and inefficient vascular network, combined with poor blood circulation, impairs its ability to dissipate heat, resulting in localized overheating⁸⁷. In contrast, healthy tissues have more efficient blood flow, allowing them to conduct and dissipate heat effectively, thus protecting them from the damaging effects of hyperthermia⁸⁸. As a result, cancer cells in the targeted area are severely damaged at temperatures ranging from 41°C to 46°C, whereas healthy tissue remains relatively unaffected at these temperatures⁸⁹. Thermotherapy capitalizes on this property by using localized high heat to target tumour cells, either by directly inducing cell death or by thermally promoting tissue repair.

In the context of OC, magnetothermolysis has demonstrated distinct advantages. As OC often originates in the pelvis and readily metastasizes to the peritoneal cavity, MNPs have been shown to efficiently concentrate within tumour lesions in both the pelvic and abdominal cavities. The magnetothermal effect is utilized to regulate the temperature at the tumour site within a precise range of 42–45 °C⁹⁰. In OC mouse models, this therapy has been shown to increase tumour cell apoptosis by over 50%, while simultaneously reducing damage to adjacent healthy organs, such as the uterus and bladder, within the pelvic cavity⁹¹. Furthermore, the localized thermal effect enhances OC cells’ sensitivity to commonly used chemotherapeutic agents, such as cisplatin and paclitaxel, thereby boosting chemotherapy efficacy by 30–40%⁹². This approach offers a novel direction for optimizing comprehensive treatment strategies for OC. In the clinical translation of magnetothermolysis, iron oxide nanoparticles (γ-Fe₂O₃) have been employed for over a decade, demonstrating notable efficacy in glioblastoma treatment. This γ-Fe₂O₃-based magnetothermolysis protocol has been approved for clinical use in Europe, with increasing interest in its oncological value and strong developmental momentum⁹³. Currently, research into magnetothermotherapy for OC remains in the preclinical stage. However, multiple research teams are preparing to initiate early-phase clinical trials to systematically evaluate its safety and efficacy in treating human OC. In summary, the multifunctional properties of MNPs in thermotherapy offer potent and minimally invasive novel solutions for cancer treatment. Ongoing advancements in related research and technologies are expected to broaden the application of MNPs in magnetothermotherapy, thereby improving cancer treatment outcomes and enhancing long-term patient prognosis.

Combined therapy with MNPs and immunotherapy

MNPs have proven effective in tumour detection and therapy assessment, primarily as MRI contrast agents. They allow real-time, dynamic monitoring of immune cell distribution and activity throughout the body, offering direct evidence of immune response progression⁹⁴. By modifying their surface, MNPs can selectively bind to tumour markers or immune cells, aiding early tumour identification and providing crucial support for assessing therapeutic efficacy⁹⁵. This method overcomes the limitations of traditional diagnostic approaches, enhancing specificity and efficiency, and laying the foundation for targeted treatment strategies.

In the therapeutic context, MNPs significantly enhance immunotherapy (Fig. 5). They enable precise delivery of immunomodulators such as cytokines, antibodies, and vaccines to targeted tissues or cells, improving efficacy and minimizing side effects. Through surface-modified antibodies that recognize target cells, MNPs facilitate the isolation of specific immune cells like T cells and NK cells, creating the conditions for their expansion and reinfusion⁹⁶. MNPs also serve as scaffolds during in vitro immune cell expansion, promoting cell proliferation and activation⁹⁷. Under alternating magnetic fields, MNPs generate localized heat, which directly kills tumour cells, releases antigens, and induces immunogenic cell death, triggering immune responses, while also enhancing the effects of immune checkpoint inhibitors⁹⁸. Additionally, MNPs can deliver tumour antigens to antigen-presenting cells, like dendritic cells, stimulating a stronger anti-cancer immune response⁹⁹. Some MNPs function as immune adjuvants, improving vaccine efficacy¹⁰⁰. Furthermore, they can deliver PD-1/PD-L1 inhibitors directly to tumour sites, minimizing systemic side effects¹⁰¹. MNPs also help modulate the tumour microenvironment by targeting immunosuppressive factors, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)¹⁰², or by enhancing vascular permeability and promoting immune cell infiltration¹⁰³.

Fig. 5.

MNPs enhance immunotherapy through various pathways.

In OC combination therapies, MNPs have shown remarkable effectiveness. For example, CA125-targeted MNPs loaded with anti-PD-L1 antibodies increased antibody concentration in the tumour microenvironment by fivefold and CD8⁺ T cell infiltration by 4.2-fold, leading to over 65% tumour growth inhibition¹⁰⁴. Magnetic hyperthermia combined with dendritic cell vaccines reduced tumour recurrence by 40%. However, assessing MNPs’ biocompatibility and degradation properties is crucial to minimizing long-term toxicity risks.

Given the variability in immunotherapy and nanomedicine efficacy, influenced by patients’ genetic characteristics, immunological profiles, and disease stages, integrating personalized medical technologies is essential for optimizing treatment outcomes. Genomic variations can directly affect immune responses to therapy, underscoring the need for precise screening based on patient-specific biomarkers. Research teams have made substantial progress in this area. A group from Seoul National University identified tumours sensitive to magnetothermal therapy by evaluating calreticulin (CRT) expression levels in tumour tissues, thus excluding ineffective treatments. They developed 7 nm superparamagnetic iron oxide nanoparticles (MnZn-SPION-7) that induce local hyperthermia (42–47 °C) using alternating magnetic fields, activating anti-tumour immunity. Real-time MRI monitoring of particle distribution was used to regulate thermal dosage and minimize normal tissue damage. In vivo studies showed a 66% reduction in tumour volume, with T2-weighted imaging clearly delineating tumour boundary changes. The induced hyperthermia triggered the release of damage-associated molecular patterns (DAMPs) such as CRT and HMGB1, facilitating dendritic cell maturation and enhancing CD8 + T cell infiltration, thus creating a “hot tumour” microenvironment¹⁰⁵. In parallel, a team from Johns Hopkins University analyzed the correlation between pre-treatment PD-L1 expression in tumours and the uptake of PD-L1-targeted NaGdF₄ nanoparticles to predict treatment response. Surface-modified with the PD-L1-blocking peptide CALNNCVRARTR, this nanoparticle selectively binds to PD-L1 on tumour cells, enhancing tumour enrichment via magnetic guidance and reducing drug dosage by 70%. The release of Gd³⁺ in the acidic tumour microenvironment improved MRI contrast and suppressed M2-type polarization of TAMs, reversing the immunosuppressive environment. In vivo experiments demonstrated a 66% reduction in tumour volume and an 80% reduction in lung metastasis¹⁰⁶. Moreover, Professor Wang Ruibing and colleagues at the University of Macau proposed a ‘supramolecular engineered bacteria’ strategy. This approach combines bacteria modified with supramolecular hosts with Fe₃O₄ particles mimicking cancer cells, which are modified with supramolecular guests, through host-guest interactions. This constructs a bacterial-Fe₃O₄ supramolecular conjugate. By leveraging the dual tumour-enriching targeting capabilities of both bacterial and cancer cell membranes, enhancing the targeted colonisation of tumour tissues by the bacterial-Fe₃O₄ supramolecular conjugate. This approach combines bacterial immunotherapy with Fe-induced cell death, achieving highly efficient, precise, and low-side-effect tumour treatment¹⁰⁷.

Limitations of MNPs in the treatment of OC and possible solutions to the problem

While MNPs offer promising potential for the treatment of OC, several limitations remain that need to be addressed. One of the primary challenges is the heterogeneity of OC lesions, which leads to uneven distribution of the nanoparticles across the tumour, making it difficult to achieve comprehensive coverage of all affected areas¹⁰⁸. Tumours located deep within the abdominal cavity can be particularly challenging to target accurately, as the strength of the magnetic field attenuates with depth¹⁰⁹. In addition, the use of non-degradable MNPs can lead to their accumulation in organs such as the liver and spleen, which may trigger long-term toxicity, and it has been demonstrated that the presence of a dense tumour stroma prevents the nanoparticles from efficiently penetrating into the tumour core, thus hindering their therapeutic potential⁵⁰. More importantly, current animal models, which are insufficient to fully replicate the complexity of OC, make it difficult to predict their full efficacy in humans¹¹⁰.

To overcome these challenges, several strategies could be explored in the future (Table 2). One promising approach involves the conjugation of OC-specific antibodies, such as anti-CA125 and anti-HE4, or folate receptor ligands, to the surface of MNPs¹¹¹. These modifications could improve the targeting precision of the nanoparticles, enabling them to better identify and bind to tumour cells. Additionally, enhancing the guidance of nanoparticles to deep tumours could be achieved by utilizing gradient magnetic fields or focused ultrasound techniques, both of which would improve magnetic field penetration and precision¹¹². Another strategy involves the use of composite materials, such as Fe₃O₄@SiO₂-PLGA, which could encapsulate a degradation layer around the magnetic material¹¹³. This approach may help prevent the buildup of non-degradable nanoparticles in organs and facilitate controlled release of the encapsulated drugs. Incorporating hyaluronidase or antifibrotic agents like trabectedin could degrade the tumour stroma, allowing for better nanoparticle penetration and improved drug delivery to the tumour’s core¹¹⁴. The development of pH or enzyme-responsive nanoparticles offers another exciting possibility for triggering drug release specifically within the tumour microenvironment, where the conditions are acidic or enzyme-rich¹¹⁵. Integrating magnetic thermotherapy (using temperatures between 42–45 °C) with chemotherapeutic agents such as cisplatin could enhance the cytotoxicity of the drugs and promote more effective tumour destruction¹¹⁶. To improve the monitoring of nanoparticle distribution and therapeutic effects, combining near-infrared fluorescence, such as Cy5.5, with MRI dual-modality imaging capabilities could provide real-time, high-resolution imaging to track the nanoparticles movement within the body¹¹⁷. Finally, using patient-derived OC carcinoids to evaluate the targeting efficiency and therapeutic effectiveness of these nanoparticles could provide more clinically relevant data. This approach would ensure that the treatments are tailored to individual patients, further optimizing therapeutic outcomes.

Table 2.

Limitations in the application of MNPs in OC and potential solutions

Limitations	Existing solutions	Validation in other tumours	Reference
Difficulty in locating tumours within cavities	CA125-targeted modified MNPs; folate receptor ligand-modified MNPs	Breast cancer:Phase I clinical trials Pancreatic cancer:preclinical models (Targeted efficiency increased by 2.8-fold)	67
Toxic substances accumulate in organs such as the liver	Polyethylene glycol surface modification; Biodegradable layer encapsulating Fe₃O₄@SiO₂-PLGA	Colorectal cancer:mouse models (Liver accumulation decreased by 60%, renal excretion rate increased by 45%) Lung cancer:large animal models (No significant hepatotoxicity was demonstrated)	113
Dense matrix barriers impede permeability	Hyaluronidase degrades hyaluronic acid within the matrix; Curebitepin inhibits matrix production	Vismodegib doubles tumour penetration depth and triples drug concentration in the tumour core Breast cancer:preclinical models (Increase substrate permeability by 40%)	114

Although MNPs present an exciting avenue for OC treatment, overcoming the challenges related to targeting accuracy, nanoparticle accumulation, tumour microenvironment barriers, and model limitations will be essential. Through the development of advanced targeting strategies, novel nanoparticle formulations, and improved imaging techniques, the full potential of MNP-based therapies for OC can be realized.

Conclusions

MNPs, as MRI contrast agents, improve early detection and enable real-time monitoring of therapeutic outcomes, enhancing diagnostic accuracy¹¹⁸. These materials possess MNPs enhance early detection and real-time monitoring as MRI contrast agents, improving diagnostic accuracy. Their magnetic properties support two key functions: magnetic targeting, which increases drug concentration in tumours by 3.5-fold while reducing toxicity to healthy tissues¹¹⁹, and magnetothermia, which induces local hyperthermia (42–45 °C) to inhibit tumour growth by 68% in cisplatin-resistant models¹²⁰. Current OC treatments are hindered by the immunosuppressive tumour microenvironment, where only 12–15% of transferred T cells infiltrate tumours¹²¹. The MNP strategy overcomes this with three synergistic mechanisms: magnetic delivery of IL-12/TGF-β inhibitors, achieving 83% targeting efficiency and reversing the M2/M1 macrophage ratio (Fig. 6A)¹²²; ICD, increasing CD8⁺ T cell infiltration by 4.2-fold to form an endogenous vaccine (Fig. 6B)¹²³; and MNP-mediated activation of the cGAS-STING pathway, boosting anti-PD-L1 therapy response from 28% to 65% in BRCA1 mutations (Fig. 6C)¹²⁴.

Fig. 6. Three synergistic mechanisms to address the challenge of difficulty of immune cell access to solid tumours.

A Reverse the M2/M1 macrophage ratio; B form endogenous vaccines; C improve the response rate of BRCA1 mutation patients to anti-PD-L1 therapy.

Perspectives

Future progress in OC therapy will rely on personalized MNPs tailored to genetic profiles and tumour-specific traits. Materials science must advance safer, biodegradable systems with controlled degradation, high biocompatibility, and reduced toxicity, while also integrating MNPs with radiotherapy, photodynamic therapy, and other multimodal approaches. Clinical translation requires rigorous validation: multicenter, randomized trials for magneto-thermo-chemotherapy in recurrent disease, and early dose-escalation studies for MNP–immunotherapy combinations. Tumour heterogeneity remains a major challenge, necessitating tools such as single-cell sequencing and spatial proteomics to guide the design of ligand-modified MNPs¹²⁵. Multimodal MRI-PET imaging platforms will further enable real-time monitoring of pharmacokinetics and therapeutic effects, supporting personalized treatment adjustments¹²⁶. Ultimately, combining MNPs with immunotherapy offers promising therapeutic avenues, overcoming technical barriers through multidisciplinary collaboration remains essential for clinical breakthroughs.

Author contributions

L.Y. and D.J.T. performed the literature search. L.Y. wrote the manuscript, and prepared Figures 1-3. F.Y.N. and M.X. prepared Figure 4. L.Z.H. revised the manuscript. L.Y. and Y.Y. designed the study and conceived and revised the manuscript. All authors contributed to the article and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Competing interests

The authors declare no competing interests.