ROS regulation in gliomas: implications for treatment strategies

Gliomas are the most common primary malignant tumours of the central nervous system (CNS), accounting for approximately 30% of all primary brain and CNS tumours and 80% of malignant brain tumours ( 1 ). According to the criteria set by the World Health Organization (WHO), the malignancy of gliomas is divided into grades I-IV, ranging from mild to severe. Glioblastomas (GBMs) are grade IV gliomas and are the most common type. Unfortunately, GBMs are also the most dangerous, with relapses being inevitable even after rigorous treatment ( 2 ). Due to the unique characteristics of the glioma tumour microenvironment (TME), such as hypoxia, the blood–brain barrier (BBB), reactive oxygen species (ROS), and tumour neovascularization, treatment often show poor efficacy ( 3 – 5 ). The standard treatment for GBMs is resection followed by radiotherapy and temozolomide (TMZ) chemotherapy, but the median survival of GBM patients is only 14.6 months ( 6 ). In addition, the humanized IgG1 monoclonal antibody bevacizumab is also commonly used in the clinical treatment of GBMs ( 7 ). According to the available studies, neither TMZ nor bevacizumab is sufficient to treat gliomas. TMZ causes alkylation of genomic DNA at the N 7 and O 6 sites of guanine and at the N 3 site of adenine. When the alkylation lesion at the guanine O 6 position is not repaired, it leads to mispairing during DNA replication, which triggers a break in the DNA strand and causes GBM cell death ( 8 – 10 ). However, O 6 -methylguanine-DNA methyltransferase (MGMT) exists in GBM cells, cleans the alkyl group produced by TMZ and repairs damaged DNA. The presence of MGMT is an important reason for the resistance of GBMs to TMZ ( 11 ). Bevacizumab targets a protein called vascular endothelial growth factor-A (VEGF-A) and slows tumour growth and proliferation by preventing tumour angiogenesis, thereby depriving GBM cells of nutrient uptake ( 7 ). However, due to tumour heterogeneity and insufficient pharmacokinetics, it is still difficult to prevent GBM recurrence with antiangiogenic therapy ( 12 – 14 ). Therefore, the search for new treatment methods for gliomas has become a hotspot of current research. ROS are reactive substances produced by oxygen reduction, including hydrogen peroxide (H 2 O 2 ), organic hydroperoxide (ROOH), singlet oxygen ( 1 O 2 ), ozone (O 3 ), superoxide anion (O 2 ˙‾ ), hydroxyl radical (OH·), and peroxyl radical (ROO·) ( 15 ), etc. Certain levels of ROS are required for cell survival and are involved in cell proliferation and differentiation ( 16 ), skeletal muscle contraction ( 17 ), immune response ( 18 ) and other processes. These physiological effects are based on the regulation of multiple signalling pathways by ROS, such as the nuclear factor-kappaB (NF-κB), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and mitogen-activated protein kinases (MAPKs) ( 19 , 20 ). The normal function of cells also depends on the ROS threshold, which represents the critical point of intracellular ROS levels ( 15 , 21 ). A level of ROS slightly below the threshold is helpful to maintain normal cell function. However, when ROS persistently accumulate abnormally beyond the threshold, they may cause irreversible oxidative damage to cells or even lead to cell death ( 21 ). In gliomas, appropriate amounts of ROS can activate growth-related signalling pathways, induce DNA mutations, and promote invasion and metastasis ( 22 – 24 ). However, it has been shown that inducing ROS accumulation leads to glioma cell death ( 25 , 26 ). In contrast, given the critical role of ROS in the cell, the depletion of ROS also makes it difficult for glioma cells to survive ( 27 , 28 ). Therefore, controlling the level of ROS becomes a potential strategy for glioma treatment. According to the literature, methods to induce massive ROS production include photodynamic therapy (PDT) ( 29 ), sonodynamic therapy (SDT) ( 30 ) and chemodynamic therapy (CDT) ( 31 ). The main approach to ROS reduction is the application of various antioxidants ( 27 , 28 , 32 ). All these methods have the potential to be used to treat gliomas. Therefore, we need to better understand the mechanisms of ROS production and clearance in gliomas, as well as their role in the glioma TME. Meanwhile, the methods based on ROS generation/scavenging also contribute to the prevention and treatment of gliomas.

The glioma TME plays an important role in the growth, invasion, recurrence and drug resistance of gliomas. Its major components include glioma cells, immune cells, signalling molecules, stromal cells, and extracellular matrix (ECM) ( 95 ). Immune cells include glioma-associated macrophages/microglia (GAMs), myeloid-derived suppressor cells (MDSCs), T cells, monocytes, neutrophils, dendritic cells (DCs) and natural killer (NK) cells. Signalling molecules include chemokines, cytokines, growth factors, and angiogenesis factors. Stromal cells include astrocytes and endothelial cells. The extracellular matrix (ECM) is a three-dimensional structure composed of fibrin, proteoglycans and other molecules that provides biochemical and structural support for surrounding cells and plays an important role in glioma invasion and metastasis ( 95 , 96 ). Among them, as important regulatory molecules, the presence of ROS have a significant impact on the glioma TME. ROS not only affect the function of immune cells ( Figure 1 ) but also participate in the process of glioma cell proliferation, invasion, metastasis and death. These studies will be discussed in this section. Figure 1 The role of ROS in immune cells in the glioma TME. (A) Under ROS stress, tumour cells secrete many cytokines, such as IL-4, IL-6, IL-10, and TGF-β, which cause macrophage immunosuppression and facilitate the recruitment of M2 tumour-associated macrophages ( 97 – 99 ). The activation of microglia is mainly manifested as the M1 type, accompanied by the release of a series of inflammatory factors ( 96 , 100 ). (B) NETs induce glioma cells to secrete IL-8 to recruit neutrophils, promote the CXCR2/PI3K/AKT/ROS signalling axis, and finally promote the formation of NETs, forming a positive feedback pathway ( 101 ). (C) Cytokines and growth factors, such as granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), IL-2, IL-1β, IL-6, and VEGF, can induce the aggregation of MDSCs in tumour hosts ( 102 , 103 ). In the plasma of GBM patients, the level of arginase is often increased, which is related to the inhibitory function of MDSCs ( 102 ). Arginase I reduces L-arginine (L-Arg) levels ( 104 ), thereby inhibiting T-cell activation ( 103 ). Nitric oxide synthase 2 (NOS2) is another major catabolic enzyme for L-Arg metabolism in MDSCs ( 105 ). MDSCs also secrete NO and ROS, which induce T-cell inhibition ( 105 ). MDSCs also indirectly affect the activation of T cells by inducing Tregs ( 103 ). CD4 + effector memory T cells (CD4 + T EM ) infiltrated by GBM strongly upregulate PD-1, and the corresponding ligand PD-L1 is expressed in MDSCs from tumours, which are involved in functional T-cell exhaustion ( 106 ). (D) The increase in mtROS causes mitochondrial DNA damage and upregulates the expression of PD-L1 to inhibit T-cell activation ( 97 , 107 ). ROS produced by Tregs can suppress effector T cells (CD4 + and CD8 + ). Effector T cells can induce an increase in ROS in tumour cells through IFN-γ and TNF-α, which can damage tumour cell DNA and lead to tumour cell death. Tregs themselves are more resistant to oxidative stress due to the increased activity of the antioxidant system, for example, by increasing GSH and upregulating NRF2 ( 108 ). Adenosine produced by Tregs can also inhibit effector T-cell function in an A2AR-dependent manner ( 109 ). (E) ROS induce the proliferation of MDSCs and inhibit NK cell function ( 110 ). In addition, high levels of ROS promote PD-L1 expression on cancer cells, thereby inactivating NK cells ( 111 ). (F) High levels of ROS can disrupt antigen presentation between T cells and DCs, which in turn affects the recognition of tumour antigens by T cells ( 98 , 108 ). 3.1 GAMs Macrophages and microglia are important cell types in the immune system. Macrophages are primarily derived from bone marrow-resident haematopoietic stem cells ( 112 ). After entering the blood, mature mononuclear macrophages can settle in different tissues, such as the liver, lung, brain, lymph nodes and other organs and tissues, at which time they will become macrophages. Macrophages are involved in phagocytosis and clearance of pathogenic microorganisms, necrotic tissues, and secretion of a variety of inflammatory mediators involved in immune regulation and tissue repair ( 113 – 115 ). Microglia are induced by the colony-stimulating factor 1 receptor (CSF1R) and are generated from red myeloid progenitors of the yolk sac. They are self-renewing and reside in the CNS for a long time ( 116 ). Microglia play an important role in maintaining the homeostasis of the nervous system, including phagocytosis ( 117 ), promoting synapse formation ( 118 ), and supplying nutrients ( 119 ). In the TME, macrophages can manifest as the M1 type (characterized by inflammatory and antitumour responses) or M2 type (involved in the repair of damaged tissues and anti-inflammation), but the TME tends to induce the differentiation of macro

T cells are members of the adaptive immune system that respond to antigens presented by antigen-presenting cells such as DCs and macrophages ( 168 ). T cells can be divided into CD4 + T cells and CD8 + T cells based on surface markers and function ( 169 ). CD4 + T cells have antigen receptors on their surface, which can recognize antigen fragments presented by MHC class II molecules on the surface of antigen-presenting cells and exert immune functions by activating other types of immune cells. CD8 + T cells generally refer to CTLs that can directly kill infected cells by MHC class I molecules ( 170 ). Regulatory T cells (Tregs) are a subset of CD4 + T cells that express the transcription factor forkhead box protein 3 (FOXP3) and play a role in inhibiting pathological immune responses and maintaining homeostasis in the body ( 171 ). In tumours, CD4 + T cells mainly activate other immune cells, such as CD8 + T cells and NK cells, to enhance the immune response ( 172 ). CD4 + T cells can secrete cytokines, such as interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), which directly kills tumour cells ( 173 ). CD8 + T cells carry specific T-cell antigen receptors (TCRs) that recognize and bind to tumour cells expressing specific antigens, thereby releasing cytotoxins, such as perforin and granzyme, to directly kill tumour cells ( 174 ). In addition, CD8 + T cells can also secrete cytokines, such as IFN-γ and TNF-α, which directly inhibit tumour cell growth and proliferation ( 175 ). Tregs play an indispensable role in maintaining the homeostasis of the immune system. Tregs suppress other immune cells and prevent excessive immune responses by producing inhibitory cytokines such as IL-10, IL-35, and TGF-β. However, overactive Tregs in turn limit the antitumour ability of immune cells ( 176 ). In gliomas, T-cell dysfunction is often caused by the strong immune escape ability of glioma cells. Some studies have shown that human GBM cells are capable of producing the immunosuppressive factor TGF-β ( 177 ), which inhibits T-cell activation, thereby weakening the immune response ( 178 ). In addition, the human glioma TME has many immunosuppressive cells, such as M2 macrophages and Tregs, whose presence usually inhibits the activity and function of T cells and is associated with reduced overall survival of patients ( 179 – 181 ). Moreover, human glioma cells often express immune escape sites on the surface, such as PD-L1 and B7 homologue 3 (B7-H3), which can bind to immune checkpoint receptors, thereby inhibiting the activity and function of T cells ( 182 ). ROS play an important role in regulating T-cell function and activity. Low levels of ROS can promote the activation and proliferation of T cells to enhance immune responses ( 183 ). However, higher levels of ROS can inhibit the secretion of cytokines by T cells and induce apoptosis ( 184 ). In the TME, excessive ROS may induce apoptosis of T cells, leading to decreased antitumour ability. For example, ROS produced by neutrophils or tumour cells can be transferred to T cells and cause OS, thereby causing hyporeactivity of T cells in cancer patients ( 185 ). In mouse glioma models, the administration of hyperbaric oxygen (HBO) can induce the generation of ROS in the thymus, which subsequently inhibits the generation of CD3 + T cells and promotes glioma growth in vivo ( 186 ). Therefore, high levels of ROS in the TME may lead to impaired T-cell function, which in turn enhances tumour escape. Targeting ROS in the TME to enhance the killing ability of T cells may be a potential therapeutic option.

DCs, which differentiate from bone marrow haematopoietic stem cells through common DC progenitors (CDPs), play an important immunomodulatory role by presenting antigens ( 206 ). In tissues, DCs are usually naturally present and are considered to serve as a bridge connecting innate and adaptive immunity and are able to promote the transformation of innate to adaptive immune responses ( 207 ). Innate immunity refers to the immunity possessed by individuals at birth, which has a wide range of effects and is not triggered by specific antigens ( 208 ). Adaptive immunity is mainly the ability to respond to and adapt to a specific antigen or pathogen, which is achieved through T-cell-mediated cellular immunity and antibody-mediated humoral immunity ( 209 ). Tumour formation is often accompanied by the expression of tumour antigens. Tumour antigens can be captured and processed by DCs and subsequently presented to naive T cells to induce their proliferation and differentiation into effector cells, such as CD8 + T cells, which subsequently kill the tumours ( 210 ). Furthermore, DCs can produce a variety of immune stimulating factors, such as cytokines and chemokines, which induce DCs and NK cells to reach inflammatory sites ( 211 ), as well as induce the activation of tumour-specific T cells ( 212 ). Antigens released by glioma cells can be captured and processed by DCs, presented to T cells, and activate effector T-cell function ( 213 ). However, glioma cells can often evade immune surveillance by inhibiting the maturation of DCs. Studies have shown that tumour-conditioned medium (TCM) collected from the supernatant of human primary glioma cells can upregulate the expression of suppressor of cytokine signalling 1 (SOCS1) in DCs and then inhibit the NF-κB signalling pathway, thereby limiting the maturation of DCs. The subsequent suppression of T-cell activity, as well as IFN-γ secretion, results in immune escape of glioma cells ( 214 ). A previous study revealed that mouse gliomas have the ability to secrete cell factors including TGF-β and IL-10 ( 215 ). These factors are known to impede the maturation and functionality of DCs within the TME ( 216 ). In addition, recent studies on the role of DCs in the progression of human GBMs have focused on the maintenance of DC homeostasis. Overexpression of NRF2 in DCs leads to the inhibition of DC maturation and subsequently reduces effector T-cell activation, which may be related to the decrease in ROS levels mediated by NRF2. In contrast, inhibition of NRF2 promotes the maturation of CD80 + and CD86 + DCs ( 217 ).

The threshold of ROS is very important in cancer therapy. When ROS produced by tumour cells exceed a certain threshold and cannot be detoxified by antioxidants, it results in high levels of OS, which drives cancer cell death or cause them to become more sensitive to treatment. However, a low level of ROS in tumour cells contributes to their growth, proliferation, invasion and metastasis ( 236 ). Therefore, tumour cells need to maintain their ROS levels to maintain their survival and invasive abilities ( 237 ). A study of tumour tissues and blood samples from glioma patients found that abnormal increases in ROS caused DNA damage in glioma cells, resulting in high expression of the DNA damage marker 8-oxo-deoxyguanosine (8-oxo-dG) and low expression of the epigenetic marker 5-methylcytosine (m5C). This is associated with increased malignancy of gliomas ( 22 ). In mouse models, glioma cells can overexpress aquaporin 8 (AQP8), which increases ROS levels, resulting in decreased expression of phosphatase and tensin homolog (PTEN) and increased expression of phosphorylated (p)-AKT, thereby promoting the growth and proliferation of gliomas ( 23 ). Moreover, the production of a significant amount of ROS induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) can activate the MAPK pathway and cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathways, subsequently enhancing the in vitro migration and invasion capability of glioma cells ( 24 ). In contrast, high levels of ROS activate regulated glioma cell death programs, including apoptosis, necrosis, autophagy, ferroptosis, etc. For example, in vitro , salinomycin can activate p53, trigger the opening of mitochondrial permeability transition pore (mPTP), and induce the production and accumulation of mtROS, leading to the necrosis of glioma cells ( 25 ). The activation of transient receptor potential mucolipin 1 (TRPML1) inhibits autophagy in glioma cells in vitro , leading to ROS production and subsequent induction of apoptosis ( 238 ). Similarly, the increase in ROS induced by isoaaptamine also leads to apoptosis and autophagy in GBM cells in vitro ( 26 ). Furthermore, the heat shock protein 90 (HSP90) and dynamin-related protein 1 (DRP1) increase ROS production by regulating the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) and mitochondrial morphology, leading to ferroptosis of gliomas in mice in vitro and in vivo ( 239 ). Glioma stem-like cells (GSCs) are a subpopulation of GBM cells with stem cell characteristics. They have self-renewal, tumourigenicity and multidirectional differentiation potential and are closely related to the occurrence, development, treatment resistance and recurrence of GBMs ( 240 ). Many studies have confirmed that ROS are involved in the proliferation, self-renewal and differentiation of GSCs ( 241 , 242 ). In a study conducted on human-derived GSCs, it was found that TGF-β upregulated the expression of the NOX4 gene, leading to the generation of ROS. Consequently, this ROS generation promoted GSC proliferation and maintained their stem cell state ( 241 ). Other studies have shown that serum stimulation in an in vitro environment is able to cause an increase in mitochondrial ROS within GSCs and modulate differentiation signalling pathways in GSCs. Interestingly, in the in vivo environment, increased ROS could greatly enhance glioma formation, which may be related to the activation of the NF-κB pathway by ROS ( 243 ). Compared with other tumour cells, GSCs have stronger antioxidant capacity ( 47 ). In vitro , the highly expressed antioxidant protein PRDX4 was able to mitigate OS in GSCs by reducing ROS generated by the protein folding process ( 47 , 244 ). Furthermore, GSCs also inhibit mitochondrial respiration by increasing the expression of mitochondrial uncoupling protein 2 (UCP2), thereby alleviating OS caused by high levels of intracellular ROS and ensuring their own survival ( 245 ). However, the understanding of the ROS threshold in cancer cells is still unclear. Measurement of the ROS threshold requires the consideration of multiple factors, including the concentration and type of ROS, the activity of intracellular antioxidant enzymes, and the type and physiological state of tumour cells ( 246 – 249 ). Therefore, more studies are needed to fully assess ROS thresholds and determine their impact on tumour cells. Overall, both ROS and thresholds play a crucial role in glioma cells. This provides a new research direction for ROS-based glioma therapy.

Ultrasound (US) is a kind of mechanical vibration wave with strong tissue penetration ability that has been widely used in ultrasound imaging and ultrasound therapy. Among the US-derived techniques, SDT based on ROS production is a good strategy. Research on SDT began in the 1990s ( 289 , 290 ). Based on the bibliometric analysis of SDT, studies have shown that since 2000, SDT has experienced rapid growth and has mainly focused on the fields of nanomaterials and cancer treatment, achieving significant results ( 291 ). The mechanism of SDT is to use low-frequency ultrasound to trigger sonosensitizers that accumulate at the tumour site, producing ROS and cavitation bubbles to kill the tumours. These ROS produce significant toxic effects on tumour cells in the 1 μm range ( 292 , 293 ). The advantage of SDT is mainly that ultrasound can penetrate to a depth of 10 cm, which can kill tumours in deeper locations ( 294 , 295 ). At present, most of the sonosensitizers used in reported SDT are photosensitizers or are derived from photosensitizers ( 296 ). However, SDT also has difficulty achieving the ideal tumour killing effect due to the presence of the BBB and the poor targeting effect of sonosensitizers such as porphyrins ( 297 ). Notably, TMZ can not only penetrate the BBB but also act as a sonosensitizer to induce necroptosis in GBMs. This provides new potential options for treating GBMs with SDT ( 293 ). According to the literature, although SDT has been studied in gliomas for less than 20 years, it has shown promising efficacy in preclinical studies ( 30 , 298 , 299 ). However, due to the maturity of the technology and the factors of ultrasound equipment and other objective reasons, the research results of SDT are less than those of PDT, and clinical research is also in its infancy. At present, there are three clinical trials of SDT in gliomas under recruitment (based on clinicaltrials.gov), as shown in Table 2 . More clinical trials are needed to verify the efficacy of SDT in the glioma treatment.

The BBB is a physical, chemical and biological barrier structure formed by capillary endothelial cells in the brain, surrounding astrocytes and muscle rings. The main function of the BBB is to maintain the stability of the brain environment, regulate the entry of nutrients, and prevent harmful substances from entering the brain through the blood ( 308 , 309 ). Brain endothelial cells are composed of hydrophobic lipid bilayers with tight junctions. Therefore, drugs with large polarity and molecular weight often have difficulty passing the BBB ( 310 ). However, research has shown that human glioma cells can infiltrate through the perivascular space and extensively invade the brain away from the tumour mass. In this process, glioma cells displace the end feet of astrocytes, thereby disrupting the BBB, which may be beneficial for drug therapy ( 311 , 312 ). However, effectively overcoming the limitations of the BBB remains a challenge. Currently, nanodrug delivery platforms ( 313 ), microbubble-enhanced focused ultrasound (MB-FUS) ( 314 ) and magnetic resonance-guided focused ultrasound (MRg-FUS) ( 315 ) are three promising approaches to break through the BBB. Nanotechnology is the study and application of particles or structures between 1 and 100 nm, where it can maximize drug transport and targeted delivery ( 316 – 318 ). Nanodrug delivery platforms are the application of nanotechnology in medicine. In general, nanodrug delivery platforms are usually composed of nanocores, nanocarriers, targeting ligands, drugs and surface modifications or may not completely contain these parts. Among them, the nanocore is the main component of the platform, mainly serving to support and stabilize the nanodrug delivery platform. It can be composed of materials such as gold ( 319 ), silicon ( 320 ), magnetic materials ( 321 ), etc. Nanocarriers refer to carriers that carry drugs on nanocores. An ideal nanocarrier can stably encapsulate drugs inside and release them at the appropriate time ( 322 ). Types of nanocarriers include gold nanoparticles, magnetic nanoparticles, carbon nanotubes, polymer micelles, and liposomes ( 323 ), etc. Targeting ligands attached to the nanocore include antibodies ( 324 ) and targeting peptides ( 325 ), which can precisely target the target. Nanocarriers can carry drugs, which include PSs such as chlorin e6 (Ce6) ( 326 ), immune checkpoint inhibitors such as nivolumab ( 327 ), and chemotherapy drugs such as doxorubicin (DOX) ( 328 ). Surface modification refers to the modification of the surface of the nanoplatform, such as polyethylene glycol (PEG), to enhance the hydropathy, stability, and biocompatibility of the nanoplatform and improve the retention time in vivo ( 329 ). In general, a well-functioning nanodrug delivery platform can typically enhance the therapeutic effects of PDT ( 330 ), SDT ( 331 ), and CDT ( 332 ) for the treatment of glioma. Moreover, optimizing key components of nanodrug delivery platforms can be an effective strategy to break through the BBB. First, the targeting of the nanoplatform should be enhanced. Transferrin (TF), for example, targets a transferrin receptor (TFR) that is overexpressed on the surface of brain capillary endothelial cells and malignant brain tumours. Related studies have shown that TF-bound nanoplatforms can effectively cross the BBB and target gliomas ( 333 , 334 ). Second, the development of new nanocarriers, such as nanotubes, gold nanoparticles, and magnetic nanoparticles, makes it easier for drugs to reach the glioma site ( 335 – 337 ). Furthermore, polymers such as polyethylene glycol (PEG) and polylactic-co-glycolic acid (PLGA) can be used to encapsulate the drug to allow crossing of the BBB. The advantages of such polymers are good biocompatibility, easy surface modification, etc., and the ability to control the rate of drug release ( 329 , 338 ). When a nanodrug delivery platform is combined with PDT, SDT, and CDT, it will greatly increase the targeting ability of the three therapeutic strategies and the level of ROS production, leading to a “1 + 1 > 2” therapeutic effect. The summary of glioma-related research on the nanodrug delivery platforms combined with PDT, SDT, and CDT is shown in Table 3 . Table 3 Summary of nanodrug delivery platforms used for glioma PDT/SDT/CDT. Categories Nanocarriers Drugs Targeting ligands Target receptors Results References PDT MRN [Ru(bpy) 2 (tip)] 2+ TF, aptamer AS1411 TFR, nucleolin The glioma cells undergo apoptosis. ( 334 ) nanotube IR780, DOX ——— ——— The glioma cells undergo apoptosis. ( 335 ) AuNs ICG, DOX TF TFR It effectively kills glioma cells. ( 336 ) GuIX nanoparticle porphyrin molecule KDKPPR NRP-1 Glioma vessels are occluded, causing growth delay. ( 337 ) polyethylene glycol IR780, camptothecin iRGD peptide αvβ3/5, NRP-1 The glioma cells undergo apoptosis. ( 339 ) albumin CAP _____ _____ The glioma cells undergo apoptosis and necrosis. ( 340 ) lipidosome Ce6, LOMs _____ _____ The generation of

ROS are products of cellular redox and play important functions in cells. Excessively high or low ROS levels are detrimental to cell survival. That is, there is a threshold for intracellular ROS, and when a large accumulation of ROS exceeds the threshold and cannot be neutralized by the antioxidant defence system, it leads to OS and thus cell death. For gliomas, there is also a threshold for ROS. Appropriate ROS levels can aid survival, but high levels of ROS can also lead to their own death. Therefore, ROS-based therapies are particularly important. Currently, there are two common therapeutic approaches involving ROS in the therapy of glioma, which are increasing ROS levels to induce cell death or using antioxidants to inhibit progression. In terms of increasing ROS, PDT/SDT/CDT is the representative approach. With the development of modern nanotechnology, the corresponding drugs can better pass through the BBB. Preclinical studies have shown that PDT/SDT/CDT combined with nanotechnology shows potent antiglioma effects and has good potential for clinical application. Conversely, ROS reduction using antioxidants has also been shown to inhibit glioma initiation and progression. Nonetheless, both strategies have limitations. In addition to the unclear clinical efficacy of antioxidants for cancer treatment reported in the literature, there are also issues such as the uncertain toxicity and biosafety of nanomaterials ( 374 , 375 ), and the uncertain stability and retention time of nanodrug delivery platforms ( 376 ). Therefore, in the future development of nanodrug delivery platforms targeting gliomas, it is necessary to enhance the targeting and stability of nanoparticles and improve the ability to cross the BBB and biosafety to provide effective treatment while reducing adverse reactions. At present, although there are still many obstacles to ROS-based therapy, ROS still have the potential to be widely used as a therapeutic target for gliomas.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.