Photodynamic Therapy in Glioblastoma: Current Insights and Emerging Molecular Targets

Nazar Vasyliv *¹, Oleksandr Tverdokhlib ², Philip Boughton ³

 

1. Centre for Clinical Brain Sciences, University of Edinburgh, University of Glasgow Affiliate, WWCRC, Scientific CEO, Global Alliance for Neurosurgical & Brain Cancer Research Innovations, Edinburgh, United Kingdom.

2. Research Data Analyst, CFO, Global Alliance for Neurosurgical & Brain Cancer Research Innovations, Edinburgh, United Kingdom.

3. GSI-Lab Head, Sydney Spine Institute, Pharmacy Project Lead Engineer & Research Affiliate, Faculty of Medicine & Health, The University of Sydney, Australia.

 

*Correspondence to: Mr Nazar Vasyliv, MD, MSc, PhD.  N.Vasyliv@sms.ed.ac.uk.

Copyright

© 2025 Mr Nazar Vasyliv, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 28 Apr 2025

Published: 02 May 2025

DOI: https://doi.org/10.5281/zenodo.15688054

Abstract

Glioblastoma (GBM), a highly aggressive and treatment-refractory tumour of the central nervous system, remains one of the most difficult cancers to treat. Despite significant advancements in surgery, radiation therapy, and chemotherapy, GBM's inherent resistance mechanisms result in poor prognosis and high recurrence rates. Photodynamic therapy (PDT), a promising treatment strategy based on the activation of photosensitizers with light to generate reactive oxygen species (ROS), offers a potential alternative to conventional therapies. However, its clinical application is constrained by limited light penetration, tumour heterogeneity, and resistance mechanisms. Recent insights into the molecular biology of GBM, particularly the role of ubiquitination and deubiquitination in regulating cellular responses to PDT, have opened new avenues for optimizing treatment efficacy. This review examines the mechanisms underlying PDT-induced cell death, the role of ubiquitination in modulating PDT responses, and the potential for enhancing PDT through novel molecular targets and combination approaches.

Introduction

Glioblastoma represents one of the most formidable healthcare challenges globally, accounting for approximately 15% of all primary brain tumours and affecting over 200,000 patients annually [1]. Despite advances in understanding the molecular biology of GBM, therapeutic options remain limited, with a median survival of just 12–18 months post-diagnosis. This survival rate has remained largely unchanged for decades, underscoring the urgent need for innovative treatments. Financial investment in GBM research is significantly lower than for other cancers, limiting the ability to develop novel and effective therapies [2]. PDT presents a promising avenue, but several factors, including the blood-brain barrier (BBB), tumour microenvironment, and tumour heterogeneity, hinder its widespread clinical adoption.

Although GBM predominantly affects adults, paediatric GBM presents distinct molecular and clinical features. Paediatric gliomas often exhibit mutations in the p53, IDH1, and H3F3A genes, contributing to their differential response to treatment [3]. Moreover, the tumour microenvironment in paediatric cases is more immunosuppressive, requiring tailored therapeutic approaches. In keeping with pediatric therapeutic best practices and ethical constraints, the PDT approach must be compatible with minimally invasive strategies and avoid leading to serious short-term or long-term complications.

Like photosynthesis, PDT involves the use of light to induce singlet oxygen formation. This singlet oxygen can then lead to the formation of ROS. This photochemical reaction occurs in the presence of porphyrins, vitamins, and other organic and inorganic molecules or agents (Tanaka and Nakamura, 2021).

PDT using porphyrin photosensitizers has demonstrated quantified targeted effectiveness against a range of infective species: bacterial, fungal, biofilm, and cancer cells [4].

PDT has also shown promise in paediatric gliomas due to its ability to specifically target tumour cells with minimal systemic toxicity, but further research is needed to elucidate the unique metabolic and molecular features of paediatric GBM that influence PDT outcomes [5].

PDT offers a targeted approach to GBM by utilizing photosensitizers that preferentially accumulate in tumour cells. Upon light activation, these photosensitizers generate ROS that can induce direct tumour cell death through apoptosis, necrosis, or autophagy [6]. The selective uptake of photosensitizers by tumour cells is influenced by several factors, including the tumour microenvironment, the expression of specific transporters, and metabolic activity [7].

The intrinsic molecular pathways governing PDT-induced tumour cell death are complex, involving not only ROS generation but also a variety of intracellular signalling pathways.

Recent studies have revealed that PDT-induced stress responses are closely linked to the regulation of protein stability via the ubiquitin-proteasome system (UPS) [8]. Ubiquitination, the process by which ubiquitin molecules are covalently attached to target proteins, regulates various cellular processes including cell cycle progression, apoptosis, and DNA repair [9]. In the context of PDT, ubiquitination plays a crucial role in modulating cellular responses to oxidative stress by regulating the degradation of key proteins involved in stress response and cell death pathways.

Ubiquitin-proteasome system dysregulation can affect tumour cell sensitivity to PDT, as certain anti-apoptotic proteins may evade degradation, promoting tumour survival even after PDT-induced damage.

Deubiquitinating enzymes (DUBs), which remove ubiquitin chains from target proteins, also modulate the cellular response to PDT. DUBs such as USP7 and USP9X have been shown to stabilize pro-survival proteins like p53 and Bcl-2, thereby enhancing resistance to PDT-induced cell death [10]. These findings highlight the potential for targeting the UPS and DUBs to enhance PDT efficacy and overcome resistance mechanisms in GBM.

 

Table 1. PDT Photosensitizers and Selectivity Enhancement

Photosensitizer	Mechanism of Selectivity	Target Tumour Cell Type	Challenges	References
5-Aminolevulinic Acid (5-ALA)	Metabolized to protoporphyrin IX (PpIX) in tumour cells, preferentially accumulating in GBM cells	Tumour cells with high metabolic activity and altered porphyrin biosynthesis	Limited depth of light penetration in solid tumours	Dougherty et al., 1998 [10]; Stummer et al., 2000 [11]
Photofrin	Accumulates in tumour vasculature, leading to vascular disruption and tumour necrosis	Tumour vasculature and endothelial cells	Suboptimal distribution in deeper tumour regions	Kessel et al., 2008 [12]; Ribeiro et al., 2015 [13]
Verteporfin	Targets tumour endothelial cells and macrophages, causing vascular damage	Endothelial cells and macrophages in the tumour microenvironment	Limited BBB penetration, requires specific light delivery systems	Nishimura et al., 2008 [14]; Baginski et al., 2014 [15]
Talaporfin  Sodium	Selectively accumulates in hypoxic regions of tumours, including GBM	Hypoxic regions of GBM	Requires optimization for hypoxic targeting	Watanabe et al., 2015 [16]; Nakajima et al., 2014 [17]

 

In Vitro, In Silico, and Preclinical Models for PDT Evaluation in Glioblastoma

The development and refinement of PDT for GBM demand comprehensive preclinical and clinical evaluation. In vitro, in silico, and preclinical animal models are essential for understanding the molecular mechanisms underlying PDT-induced cell death, identifying predictive biomarkers, and optimizing therapeutic strategies. These models allow for investigation into how PDT interacts with the complex molecular machinery of GBM cells, particularly the role of the ubiquitin-proteasome system (UPS) and deubiquitinating enzymes (DUBs), which regulate essential cell survival and death pathways. By targeting these mechanisms, it is possible to sensitize GBM cells to PDT and improve therapeutic outcomes.

In Vitro Models for PDT Evaluation in GBM

In vitro cell culture models, particularly using GBM cell lines such as U87MG and T98G, provide controlled environments to study PDT at the molecular level. These models allow for detailed investigation of PDT-induced cytotoxicity, the generation of ROS, and the subsequent activation of key intracellular signaling pathways, such as apoptosis, autophagy, and necroptosis.

 

Molecular Mechanisms of PDT in GBM

PDT relies on the accumulation of photosensitizers within tumour cells and their activation by light to generate ROS. These ROS cause cellular damage by modifying key macromolecules, including lipids, proteins, and DNA. At the molecular level, PDT-induced oxidative stress triggers several key pathways, including:

 

Table 2. Key Molecular Targets Influencing PDT Efficacy in GBM

Molecular Target	Role in PDT Response	Regulatory Mechanism	Potential Therapeutic Strategy	References
p53	Apoptosis regulation	Ubiquitination by MDM2	MDM2 inhibitors (e.g., Nutlin-3) to restore p53 function	[18], [31]
Bcl-2	Anti-apoptotic protein	Stabilized by USP9X	USP9X inhibitors to destabilize Bcl-2	[9], [24]
RIPK1/RIPK3	Necroptosis activation	Ubiquitinated and regulated by DUBs	Promote necroptosis via DUB inhibition	[21], [37]
ATM/ATR	DNA damage response	Ubiquitin-modulated activity	UPS inhibitors to impair DDR and enhance PDT	[20], [32]
c-Myc	Cell proliferation and survival	Regulated by SCF^βTrCP E3 ligase	Inhibit SCF^βTrCP or enhance degradation	[22]

Apoptosis: ROS activate the intrinsic mitochondrial pathway, leading to the release of pro-apoptotic factors like cytochrome c and the activation of caspases. A central regulator of apoptosis is p53, a tumour suppressor protein that is frequently mutated in GBM. Ubiquitination of p53 plays a critical role in its stability and function. Upon PDT, the UPS can facilitate the degradation of mutated or damaged p53, contributing to tumour resistance. Inhibition of E3 ubiquitin ligases such as MDM2, which promote p53 degradation, could enhance p53-mediated apoptosis in GBM cells post-PDT [18]. Disruption of p53's ubiquitination could help overcome PDT resistance mechanisms in GBM.

Autophagy: In response to ROS, GBM cells may initiate autophagy as a protective mechanism. Autophagy is regulated by several key molecular pathways, including the mTOR pathway, and involves the degradation of cellular components in lysosomes. Ubiquitination plays a role in tagging autophagic substrates for degradation. Proteins such as p62/SQSTM1 are often stabilized by ubiquitination during PDT, facilitating autophagy in GBM cells. This survival mechanism can be targeted to sensitize GBM cells to PDT-induced death [19]. Ubiquitin-protein conjugates can be manipulated to optimize autophagic flux and enhance PDT efficacy.

DNA Repair: ROS generated during PDT induce DNA damage, which triggers the DNA damage response (DDR). Proteins such as ATM, ATR, and DNA-PKcs are regulated by ubiquitination to modulate their stability and activity. In GBM, inhibiting DDR pathways could enhance PDT efficacy by preventing the repair of PDT-induced DNA lesions. DUBs such as USP1 and USP7 regulate the stability of DDR proteins, influencing their ability to repair PDT-induced DNA damage [20]. Targeting the UPS to prevent the degradation of DDR proteins could potentiate the efficacy of PDT.

Necroptosis: PDT can trigger necroptosis, a form of programmed necrosis regulated by the RIPK1/RIPK3/MLKL pathway. The role of ubiquitination in necroptosis regulation is becoming increasingly significant. RIPK1undergoes ubiquitination by various E3 ligases, which modulate its interaction with downstream signaling molecules such as RIPK3 and MLKL. Inhibition of DUBs, which remove ubiquitin chains, can enhance necroptosis and promote GBM cell death following PDT [21]. Manipulating ubiquitin conjugation pathways offers a novel strategy to enhance PDT efficacy in GBM treatment.

These molecular insights emphasize the central role of ubiquitination and DUBs in modulating the cellular response to PDT. Targeting these pathways can optimize PDT efficacy in GBM by overcoming resistance mechanisms and enhancing therapeutic outcomes.

 

In Silico Models for PDT Evaluation in GBM

In silico models, which use computational simulations to predict tumour responses to PDT, have become critical in optimizing treatment parameters and predicting therapeutic outcomes. These models incorporate the complexities of light penetration, photosensitizer distribution, and the cellular molecular responses to PDT.

 

Modeling PDT-Induced Molecular Pathways

Computational models enable researchers to simulate interactions between PDT-induced ROS and the molecular machinery of GBM cells. Specifically, these models simulate how the ubiquitin-proteasome system (UPS) regulates the degradation of proteins involved in cell cycle progression, DNA repair, and apoptosis. In the context of PDT, computational approaches can predict how changes in ubiquitin ligase activity, such as inhibition of MDM2 or SCFβTrCP, may influence the stability of proteins like p53 and c-Myc, which play critical roles in GBM cell survival [22]. By incorporating these molecular dynamics, in silico models help identify treatment strategies that enhance PDT's efficacy.

Additionally, these computational models can simulate the effects of DUB inhibition on GBM cell survival post-PDT. For example, inhibiting USP7, a DUB that stabilizes pro-survival proteins such as p53 and MDM2, could enhance PDT efficacy by promoting the degradation of these proteins [23]. These models provide a rationale for combining PDT with inhibitors targeting the UPS and DUBs to improve therapeutic outcomes in clinical settings.

 

Preclinical Animal Models for PDT Evaluation in GBM

Preclinical animal models, particularly orthotopic GBM mouse models, are essential for evaluating the in vivo efficacy of PDT. These models closely replicate the complex tumour microenvironment of GBM, including the blood-brain barrier (BBB), tumour vasculature, and hypoxic regions, all of which influence PDT treatment outcomes.

 

Role of the UPS and DUBs in Preclinical Models

In preclinical animal studies, the role of the UPS and DUBs in modulating PDT responses is increasingly recognized. For example, animal models have shown that proteasome inhibition with agents like bortezomib can increase tumour cell sensitivity to PDT by preventing the degradation of pro-apoptotic proteins. Conversely, targeting DUBs such as USP9X, which stabilize anti-apoptotic proteins like Bcl-2, can sensitize GBM cells to PDT-induced death by promoting the degradation of survival proteins [24].

Table 3. Overview of Deubiquitinating Enzymes (DUBs) in PDT Resistance

DUB	Target Protein(s)	Function in PDT	Inhibition Outcome	References
USP7	p53, MDM2	Stabilizes pro-survival proteins	Enhances PDT-induced apoptosis	[9], [23]
USP9X	Bcl-2	Promotes resistance to apoptosis	Sensitizes GBM cells to PDT	[9], [24]
USP1	DNA repair proteins	Maintains DDR signaling	Increases DNA damage post-PDT	[20]
CYLD	RIPK1	Regulates necroptosis threshold	Promotes necroptosis	[21]

 

In preclinical models, light delivery systems are optimized to overcome the challenge of light penetration in deep-seated tumours. Advanced techniques, such as fiber-optic probes and endoscopic systems, allow for precise delivery of light to the tumour site, ensuring adequate ROS generation to induce tumour cell death. Combining PDT with UPS-targeting agents may enhance therapeutic responses by promoting apoptosis and autophagy in GBM cells [25, 26]. Moreover, nanoparticle-based drug delivery systems are being explored to overcome the BBB, improving photosensitizer accumulation in GBM and enhancing PDT efficacy [27, 28].

 

Selective Illumination and the Physics of PDT Application

Efficient light delivery is a key factor in the success of PDT, particularly for tumours located in deep-seated brain regions. The limited penetration of light in tissues, especially for deeply located GBM tumours, requires innovative approaches in light delivery. The use of fiber-optic probes, endoscopic systems, and implantable devices can help overcome this limitation [29]. Furthermore, optimizing the wavelength of light is essential for ensuring that the photosensitizers are effectively activated. Near-infrared (NIR) light, which penetrates more deeply into tissues, has been shown to be particularly effective for PDT in deep-seated brain tumours [30].

The role of the UPS in regulating PDT-induced tumour cell death is increasingly recognized. Proteins involved in DNA repair, apoptosis, and oxidative stress response are tightly controlled by ubiquitination. For example, the stabilization of the tumour suppressor p53 through inhibition of its ubiquitination can enhance the apoptotic response to PDT [31]. Additionally, the removal of ubiquitin chains by DUBs can prevent the degradation of key pro-survival proteins, leading to increased resistance to PDT. Therefore, targeting the UPS and DUBs in combination with PDT could improve treatment outcomes by preventing resistance mechanisms and enhancing the tumour’s susceptibility to oxidative stress [32].

 

Optimizing PDT Dose and Delivery

The optimization of PDT involves carefully balancing light dose, photosensitizer concentration, and treatment timing to maximize tumour cell death while minimizing damage to healthy tissue. Advances in PDT optimization include the use of fractionated doses of light or photosensitizers, as well as the timing of light exposure relative to circadian rhythms, which influence the cellular response to PDT [33]. Furthermore, combining PDT with inhibitors of the UPS, such as proteasome inhibitors or DUB inhibitors, can help sensitize tumour cells to PDT-induced cell death by modulating protein degradation and apoptosis pathways [34].

Table 4. Wavelength-Dependent Optimization of Light Delivery in PDT for Glioblastoma

Wavelength Range (nm)	Light Type	Tissue Penetration Depth	Compatible Photosensitizers	Clinical Advantages	Limitations	References
400–450	Violet–Blue	<1 mm	None widely used for deep tumors	Strong PS activation	Limited penetration	[29]
630–635	Red (standard PDT)	2–5 mm	Photofrin, 5-ALA (PpIX)	Widely used, FDA-approved for other cancers	Suboptimal for deep brain tumors	[11], [12], [30]
650–690	Deep Red	5–10 mm	Talaporfin sodium, Verteporfin	Better depth, used in Japan for GBM trials	Requires precise light dosing	[14], [16], [17]
700–800	Near-Infrared (NIR-I)	Up to 20 mm	Indocyanine green, NIR dyes	Excellent depth, minimal scattering	Lower energy photons, lower ROS generation	[30], [27], [29]
800–900	Near-Infrared (NIR-II)	20–30 mm	Experimental NIR-II PSs	Potential for non-invasive deep brain access	Mostly preclinical, unapproved PSs	[30], emerging data

 

The circadian regulation of the UPS and cell cycle is particularly relevant in optimizing PDT. Studies have shown that the cellular response to PDT, including DNA repair and apoptosis, is influenced by the time of day [35]. By synchronizing PDT treatment with the natural circadian rhythm, it may be possible to enhance the efficacy of PDT and improve clinical outcomes [36].

 

Targeting Necroptosis and mediated cell-death pathways in GBM Post-PDT

Necroptosis, a regulated form of cell death, is emerging as a critical pathway in GBM’s response to PDT. Unlike apoptosis, necroptosis is initiated when apoptosis is blocked, and is often driven by receptor-interacting protein kinases (RIPKs), particularly RIPK1, RIPK3, and MLKL (Nazar Vasyliv, 2024, MAR). Ubiquitination plays a central role in regulating necroptosis, with RIPK1 and RIPK3 being substrates for ubiquitination and deubiquitination. By inhibiting DUBs such as USP7, which stabilize anti-apoptotic proteins, it may be possible to promote necroptosis in GBM stem cells and enhance the effectiveness of PDT [37]. This approach could provide an alternative form of cell death when apoptosis pathways are compromised in GBM.

Despite promising results from in vitro, in silico, and preclinical models, the clinical translation of PDT for GBM remains challenging. Key issues include limited light penetration in solid tumours and the heterogeneity of the tumour microenvironment. The BBB also presents a major obstacle for delivering photosensitizers to GBM cells. Recent advances in nanoparticle-based delivery systems are addressing these barriers by improving photosensitizer uptake in GBM cells.

Understanding the role of circadian rhythms in regulating cellular responses to PDT is another emerging area of interest. In vivo studies have shown that the timing of PDT can influence its efficacy, as circadian regulation of the UPS affects cellular sensitivity to ROS. Targeting the circadian clock and its influence on the UPS could synchronize treatment with peak tumour cell sensitivity, thus enhancing PDT outcomes [38].

 

Research Ethics and Conflict of Interest Statement

The authors affirm that the research was conducted in accordance with the highest ethical standards and institutional guidelines. No conflicts of interest, financial or otherwise, are declared by any of the authors. All authors contributed independently and impartially to the conception, design, and execution of the study.

 

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