Strategy For Photodynamic Therapy Research Articles

Photo-Facilitated Nitric Oxide-Triggered Turn-on Photodynamic Therapy for Precise Antitumor Application.

Photodynamic therapy (PDT) is a powerful strategy for tumor therapy with noninvasiveness and desirable efficacy. However, the phototoxicity of photosensitizer after the post-PDT is the major obstacle limiting the clinic applications. Herein, a nitric oxide (NO)-activatable photosensitizer is reported with turn-on PDT behavior and endoplasmic reticulum (ER) targeting ability for precise tumor therapy. Four o-thiophenediamine derivatives with reaction-tunable donor/acceptor push-pull electronic effect are established, and the systematic structure and property relationship observation reveals the following features: 1) the reactivity against NO can be improved by enhancing the electron density and further facilitated upon photo-irradiation. 2) the reactivity with NO enables the improved intramolecular charge transfer process with the evoking of photosensitizing effect. 3) only o-thiophenediamine derivative with ER enrichment behavior exhibited cancer cell ablation effect compared to photosensitizers localized in lysosome and lipid droplet. Thus, the efficient inhibition of cancer cells both in vitro and in vivo is realized based on the photo-controlled PDT strategy. This work provides more insights into developing promising activatable photosensitizers for advanced therapy based on tumor microenvironment trigger.

Modified Oxygen Metabolism Toward “Sunlight‐Friendly” Photodynamic Therapy

AbstractPhototoxicity poses a substantial challenge in photodynamic therapy, resulting in intolerable skin damage, visual impairment, and reduced quality of life. Current coping strategies, primarily focus on avoiding inappropriate photoactivation and developing targeted photosensitizers, have not effectively addressed this problem. Hence, this study aims to develop a “sunlight‐friendly” photodynamic therapy strategy. Here, 1‐methoxyphenazine methosulfate (MPMS) is innovatively identified as a key substance in achieving modified oxygen metabolism. MPMS demonstrates efficient catalytic shuttling under abnormal intracellular H2O2 levels, introducing a novel protective approach for oxygen metabolism and numerous life processes. By controlling MPMS administration, the switch of the photosensitizer states between “ON” (killing tumor cells) and “OFF” (safeguarding normal cells) can be achieved. This approach effectively mitigated phototoxicity and holds the potential for widespread clinical application.

Efficient Delivering of a Photodynamic Therapy Drug into Cellular Membranes Rationalized by Molecular Dynamics.

Photodynamic therapy (PDT) represents a most attractive therapeutic strategy to reduce side-effects of chemotherapy and improve the global quality of life of patients. Yet, many PDT drugs suffer from poor bioavailability and cellular intake, and thus, drug-delivering strategies are mandatory. In this article, we rationalize the behavior of a temoporfin-based PDT drug, commercialized under the name of Foscan, complexed by two β-cyclodextrin units, acting as drug carriers, in the presence of a lipid bilayer. Our all-atom simulations have unequivocally shown the internalization of the drug-delivering complex and suggest its possible spontaneous dissociation in the lipid bilayer core. The factors favoring penetration and dissociation have also been analyzed, together with membrane perturbation due to the interaction with the drug carrier complex. Our results confirm the suitability of this encapsulation strategy for PDT and rationalize the experimental results concerning its efficacy.

Design and Synthesis of BODIPY and Its Application in Inhibiting Intestinal Flora.

BODIPY-based photosensitizers were synthesized and tested for antimicrobial photodynamic therapy, revealing structural modifications enhancing the photodynamic therapy (PDT) effects. This research may lead to new PDT strategies for treating bacterial infections, including those resistant to traditional antibiotics, and offers insights into the prevention and treatment of Alzheimer's disease through gut microbiota regulation.

A Self-Immobilizing Photosensitizer with Long-Term Retention for Hypoxia Imaging and Enhanced Photodynamic Therapy.

The precise theranostic strategy of fluorescence imaging-guided photodynamic therapy (PDT) can effectively mitigate the adverse effect of photosensitizers in normal cells and tissues. However, low tumor enrichment and high diffusivity of photosensitizers significantly compromise the imaging accuracy and PDT effect. In this study, we have developed a nitroreductase (NTR)-activated and self-immobilizing photosensitizer CyNT-F, which showed enhanced enrichment in tumor tissues and facilitated precise and sustained imaging as well as PDT for hypoxia tumors. mPEG-b-PDPA nanomicelles encapsulating photosensitizers underwent dissociation and released CyNT-F in tumor cells. CyNT-F and NTR enzymatically reacted in situ to generate highly reactive quinone methide, subsequently covalently binding to adjacent proteins for fluorescence and PDT activation. CyNT-F exhibited longer intracellular retention (7 days) and effectively inhibited the tumor growth of solid hypoxia tumor. We believe the activatable and self-immobilizing strategy of PDT presents a novel methodology for minimizing the adverse effect and enabling spatiotemporally accurate ablation of diseased cells and tissues.

Alkyl chain length-regulated in situ intelligent nano-assemblies with AIE-active photosensitizers for photodynamic cancer therapy

Photodynamic therapy (PDT) brings new hope for the treatment of breast cancer due to few side effects and highly effective cell killing; however, the low bioavailability of traditional photosensitizers (PSs) and their dependence on oxygen severely limits their application. Aggregation-induced emission (AIE) PSs can dramatically facilitate the photosensitization effect, which can have positive impacts on tumor PDT. To-date, most AIE PSs lack tumor targeting capability and possess poor cell delivery, resulting in their use in large quantities that are harmful to healthy tissues. In this study, a series of AIE PSs based on pyridinium-substituted triphenylamine salts ( TTPAs 1–6) with different alkyl chain lengths are synthesized. Results reveal that TTPAs 1–6 promote the generation of type I and II ROS, including ·OH and 1O2. In particular, the membrane permeability and targeting of TTPAs 4-6 bearing C8-C10 side-chains are higher than TTPAs 1-3 bearing shorter alkyl chains. Additionally, they can assemble with albumin, thereby forming nanoparticles (TTPA 4–6 NPs) in situ in blood, which significantly facilitates mitochondrial-targeting and strong ROS generation ability. Moreover, the TTPA 4–6 NPs are pH-responsive, allowing for increased accumulation or endocytosis of the tumor and enhancing the imaging or therapeutic effect. Therefore, the in vivo distributions of TTPA 4–6 NPs are visually enriched in tumor sites and exhibited excellent PDT efficacy. This work demonstrates a novel strategy for AIE PDT and has the potential to play an essential role in clinical applications using nano-delivery systems.

Golgi apparatus-targeted BODIPY-based photosensitizer synergized with glutaminase inhibition for enhanced photodynamic therapy

Photodynamic therapy (PDT) is a precise and less toxic side effect treatment strategy. However, the inherently short lifespan and constrained diffusion range of reactive oxygen species within the cellular milieu can attenuate the therapeutic efficacy of cytoplasmic photosensitizers. Organelle-targeted PDT is thus proposed. Although the essence of PDT is the photosensitization reaction accompanied by biological effects involving aerobic molecules, mitochondria-targeted PDT may lead to the emergence of drug resistance in tumor cells triggered by mitochondrial damage. Thus, developing more types of organelle-targeted PDT strategies is the key to avoiding this problem. Herein, a fluoroboron dipyrrole-based photosensitizer, OFBDP, with Golgi apparatus-targeted and PDT ability is designed and synthesized. Furthermore, considering the effect of high concentrations of reduced glutathione in tumor cells, the addition of glutaminase inhibitor, compound 968 (C968), synergistically enhanced the PDT efficacy of OFBDP by indirectly inhibiting intracellular glutathione synthesis through its effect on glutamine metabolism. The OFBDP/C968 combination has demonstrated an enhanced tumor ablation capability. This work generally provides a strategy for the potential of organelle-targeted PDT to improve treatment outcomes, but also contribute to the burgeoning field of subcellular photosensitizer research.

A mitochondria targeting Ir(III) complex triggers ferroptosis and autophagy for cancer therapy: A case of aggregation enhanced PDT strategy for metal complexes

Metal complexes hold significant promise in tumor diagnosis and treatment. However, their potential applications in photodynamic therapy (PDT) are hindered by issues such as poor photostability, low yield of reactive oxygen species (ROS), and aggregation-induced ROS quenching. To address these challenges, we present a molecular self-assembly strategy utilizing aggregation-induced emission (AIE) conjugates for metal complexes. As a proof of concept, we synthesized a mitochondrial-targeting cyclometalated Ir(III) photosensitizer Ir-TPE. This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups. Ir-TPE readily self-assembles into nanoaggregates in aqueous solution, leading to a significant production of ROS upon light irradiation. Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria, resulting in mitochondrial DNA damage. This damage can lead to ferroptosis and autophagy, two forms of cell death that are highly cytotoxic to cancer cells. The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS, leading to a more pronounced cytotoxic effect. In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication. This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.

Graphene-Based Photodynamic Therapy and Overcoming Cancer Resistance Mechanisms: A Comprehensive Review.

Photodynamic therapy (PDT) is a non-invasive therapy that has made significant progress in treating different diseases, including cancer, by utilizing new nanotechnology products such as graphene and its derivatives. Graphene-based materials have large surface area and photothermal effects thereby making them suitable candidates for PDT or photo-active drug carriers. The remarkable photophysical properties of graphene derivates facilitate the efficient generation of reactive oxygen species (ROS) upon light irradiation, which destroys cancer cells. Surface functionalization of graphene and its materials can also enhance their biocompatibility and anticancer activity. The paper delves into the distinct roles played by graphene-based materials in PDT such as photosensitizers (PS) and drug carriers while at the same time considers how these materials could be used to circumvent cancer resistance. This will provide readers with an extensive discussion of various pathways contributing to PDT inefficiency. Consequently, this comprehensive review underscores the vital roles that graphene and its derivatives may play in emerging PDT strategies for cancer treatment and other medical purposes. With a better comprehension of the current state of research and the existing challenges, the integration of graphene-based materials in PDT holds great promise for developing targeted, effective, and personalized cancer treatments.

Synergistic luminescent radicals and precursors as type-I photosensitizers for near-infrared fluorescence-guided tumor therapy

Near-infrared (NIR) fluorescence-guided photodynamic therapy (PDT) shows great potential as a cancer treatment modality. However, its application in solid tumors is limited by the scarcity of NIR molecules and the oxygen dependence of conventional photosensitizers. Here, two novel radical nanoparticles (TTM-3PDMAC:HTTM-3PDMAC@NPs and TTM-PDMAC:HTTM-PDMAC@NPs) are developed as type-I photosensitizers by combining luminescent radicals and their precursors. The unique encapsulation of these nanoparticles effectively addresses the limitations of radicals being insoluble and non-fluorescent in water, thus preserving the NIR emission of the radicals. Notably, the superoxide radicals generated by these nanoparticles upon light irradiation have been demonstrated to originate from both the radicals and their precursors. In vivo experiments demonstrated that TTM-3PDMAC:HTTM-3PDMAC@NPs exhibit significant efficacy in treating hypoxic tumor with minimal side effects. Overall, this PDT strategy based on synergistic combination of luminescent radicals and precursors provides novel insights for achieving accurate and efficient PDT under NIR fluorescence guidance.

Nano‐Mediated PDT as a Multifunctional Immunomodulatory Agent in the Intricate Milieu of Melanoma

AbstractThe complexity of the tumor microenvironment (TME) and nutrient competition represent the main causes of therapy resistance in cancers, including malignant melanoma (MM). Photodynamic therapy (PDT), through a cascade of events including its ability to induce significant immune responses, causes tumor eradication. However, the high pigmentation level of melanoma, lack of adequate accumulation of photosensitizers (PSs) in the target tissue as well as their nonspecific toxicity represent three main obstacles to obtaining satisfactory responses in melanoma. To prevail over these challenges, this study employs a depigmentation strategy followed by a nano‐mediated topical application of PDT using a chlorophyllin derivative as PS, focusing on the evaluation of the immunomodulatory and metabolic regulatory axes of PDT in melanoma. Photo‐immunomodulation is assessed in a melanoma mouse model using a nanocarrier system of the PS. Markers of the immunosuppressive microenvironment and T cell exhaustion, as independent immune hallmarks, are quantified. The histopathology of the spleen and skin/tumor is evaluated. The amino acid profile is quantified from normal skin or tumor biopsies using UHPLC‐MS/MS. Around 80% of the 300 nm transethosomal ferrous chlorophyllin (fC‐TEs) are retained in the tumor over 24 h upon topical application. Arbutin 2% gel not only decreased the melanin content of tumors but also regulated the expression of interleukin 12 (IL‐12), IL‐10, transforming growth factor beta (TGF‐β), and tumor necrosis factor‐alpha (TNF‐α). Additionally, the nano‐mediated PDT strategy decreased the expression of programmed cell death protein 1 (PD‐1) and its ligand 1 (PD‐L1) and reduces the activity of arginase 1 (Arg1) through an upregulation of miRNA155. A mild recruitment of megakaryocytes (MKs) is observed in the spleen of the PDT group. This special localization of MKs depicts effector immune properties. Lastly, the combination of PDT and arbutin restores the normal tissue levels of arginine (Arg), and glutamine (Gln) and lavished those of tryptophan (Trp). Nano‐mediated PDT represents a novel immunotherapeutic approach in melanoma by a triple modulation of the immune suppressive TME, immune checkpoint signaling, and reprogrammed tumor metabolism.

Red light-triggered release of ROS and carbon monoxide for combinational antibacterial application.

The abuse of antibiotics has led to the emergence of a wide range of drug-resistant bacteria. To address the challenge of drug-resistant bacterial infections and related infectious diseases, several effective antibacterial strategies have been developed. To achieve enhanced therapeutic effects, combinational treatment approaches should be employed. With this in mind, a metal-organic framework (MOF) based nanoreactor with integrated photodynamic therapy (PDT) and gas therapy which can release reactive oxygen species (ROS) and carbon monoxide (CO) under red light irradiation has been developed. The release of ROS and CO under red light irradiation exerts a preferential antibacterial effect on Gram-positive/Gram-negative bacteria. The bactericidal effects of ROS and CO on Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA) are better than ROS only, showing a combinational antibacterial effect. Furthermore, the fluorescence emission properties of porphyrin moieties can be leveraged for real-time tracking and imaging of the nanoreactors. The simple preparation procedures of this material further enhance its potential as a versatile and effective antibacterial candidate, thereby presenting a new strategy for PDT and gas combinational treatment.

Precise molecular engineering for the preparation of pyridinium photosensitizers with efficient ROS generation and photothermal conversion.

Organic photosensitizers (PSs) with aggregation-induced emission properties have great development potential in the integrated application of multi-mode diagnosis and treatment of photodynamic therapy (PDT) and photothermal therapy (PTT). However, preparing high-quality PSs with both optical and biological properties, high reactive oxygen species (ROS) and photothermal conversion ability are undoubtedly a great challenge. In this work, a series of pyridinium AIE PSs modified with benzophenone have been synthesized. A wide wavelength range of fluorescent materials was obtained by changing the conjugation and donor-acceptor strength. TPAPs5 has a significant advantage over similar compounds, and we have also identified the causes of high ROS generation and high photothermal conversion in terms of natural transition orbitals, excited state energy levels, ground-excited state configuration differences and recombination energy. Interestingly, migration of target sites was also found in biological imaging experiments, which also provided ideas for the design of double-targeted fluorescent probes. Therefore, the present work proposed an effective molecular design strategy for synergistic PDT and PTT therapy.

Singlet oxygen storage and controlled release for improving photodynamic therapy against hypoxic tumor.

Photodynamic therapy (PDT) is considered to be a promising tumor treatment method due to its non-invasiveness and low risk. However, there are two factors that affect the efficacy of this therapy. One is the light source and the other is the tumor hypoxia. An emerging PDT strategy has been developed to break these limits. This strategy is to adopt compounds, such as 2-pyridone, anthracene, and naphthalene derivatives, that have the ability to store and controlledly release the singlet oxygen (1O2) to achieve PDT in the dark. In this review, we focus on the construction strategies for integrated antitumor drugs containing these 1O2 storage/release units and photosensitizers and summarize their PDT performance in hypoxic tumors or in the dark. The methods to integrate these compounds with photosensitizers or nanocarriers are also discussed in detail to provide insightful design guidelines for the design of highly efficient antitumor systems based on 1O2 storage and controlled release.

Photodynamic Therapy Using RGD-Functionalized Quantum Dots Elicit a Potent Immune Response in a Syngeneic Mouse Model of Pancreatic Cancer.

Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy. The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody. QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors. QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses.

Deepened Photodynamic Therapy through Skin Optical Clearing Technology in the Visible Light Window.

The trade-off that shorter wavelength light facilitates the efficient generation of reactive oxygen species (ROS) from photosensitizer (PS) while facing the drawback of limited penetration depth through skin tissue restricts the further development of photodynamic therapy (PDT). Here, we address this contradiction and achieve visible-light-tailored deep PDT combined with the skin optical clearing technology. With the help of the prepared skin optical clearing gel, the refractive index inhomogeneity between skin tissue components is greatly attenuated, and the light scattering effect within the skin tissue is remarkably reduced. As a consequence, the transmittance of visible light at 600 nm through in vitro porcine skin and in vivo mouse skin after treatment increases from approximately 10 and 40 to 70 and 70%, respectively. Furthermore, in the tumor cell eradication experiment, the local ROS generation efficiency in the experimental group is several times higher than that in the control group owing to improved visible transmittance, which is thus responsible for the complete eradication of tumor cells, even when shaded by skin tissue. The results suggest that this strategy may serve as a valuable supplement to the current deep PDT strategies.

Yeast Nanoparticle‐powered Tumor Photodynamic‐Immunotherapy

Photodynamic therapy (PDT) uses a combination of light and a photosensitizing agent to destroy cancerous cells. However, the PDT alone often insufficient to elicit an effective anti-tumor response due to various factors including insufficient ROS generation and the weak induced immune response. Here, we report yeast nanoparticles (YNPs) loaded with aggregation-induced emission (AIE) photosensitizer QMC12 (YNP-QMC) for enhanced photodynamic-immunotherapy in animal models. YNPs have a strong immune adjuvant effect which could significantly activate various APCs and reverse the immunosuppressive microenvironment at tumor and tumor-draining lymph nodes (TDLNs) sites. More importantly, YNP-QMC can be attached with tumor cell antigens released from dying cells after PDT. This antigen attached nanoparticle can efficiently migrate to tumor-draining lymph nodes and activate an antigen-specific systemic antitumor immunity. In combination with anti-PD-L1, this strategy could promote the elimination of primary tumors and inhibit the growth of distant tumors. Thus, our AIE photosensitizer and adjuvant YNP-powered PDT strategy provides a simple way to enhance efficacy of PDT.

Exploring a Mitochondria Targeting, Dinuclear Cyclometalated Iridium (III) Complex for Image-Guided Photodynamic Therapy in Triple-Negative Breast Cancer Cells.

Photodynamic therapy (PDT) has emerged as an efficient and noninvasive treatment approach utilizing laser-triggered photosensitizers for combating cancer. Within this rapidly advancing field, iridium-based photosensitizers with their dual functionality as both imaging probes and PDT agents exhibit a potential for precise and targeted therapeutic interventions. However, most reported classes of Ir(III)-based photosensitizers comprise mononuclear iridium(III), with very few examples of dinuclear systems. Exploring the full potential of iridium-based dinuclear systems for PDT applications remains a challenge. Herein, we report a dinuclear Ir(III) complex (IRDI) along with a structurally similar monomer complex (IRMO) having 2-(2,4-difluorophenyl)pyridine and 4'-methyl-2,2'-bipyridine ligands. The comparative investigation of the mononuclear and dinuclear Ir(III) complexes showed similar absorption profiles, but the dinuclear derivative IRDI exhibited a higher photoluminescence quantum yield (Φp) of 0.70 compared to that of IRMO (Φp = 0.47). Further, IRDI showed a higher singlet oxygen generation quantum yield (Φs) of 0.49 compared to IRMO (Φs = 0.28), signifying the enhanced potential of the dinuclear derivative for image-guided photodynamic therapy. In vitro assessments indicate that IRDI shows efficient cellular uptake and significant photocytotoxicity in the triple-negative breast cancer cell line MDA-MB-231. In addition, the presence of a dual positive charge on the dinuclear system facilitates the inherent mitochondria-targeting ability without the need for a specific targeting group. Subcellular singlet oxygen generation by IRDI was confirmed using Si-DMA, and light-activated cellular apoptosis via ROS-mediated PDT was verified through various live-dead assays performed in the presence and absence of the singlet oxygen scavenger NaN3. Further, the mechanism of cell death was elucidated by an annexin V-FITC/PI flow cytometric assay and by investigating the cytochrome c release from mitochondria using Western blot analysis. Thus, the dinuclear complex designed to enhance spin-orbit coupling with minimal excitonic coupling represents a promising strategy for efficient image-guided PDT using iridium complexes.

InN@In2S3 Core-Shell nanorod for oxygen-free and penetration depth-unrestricted photodynamic therapy against glioblastoma

Photodynamic therapy (PDT) is among the most promising antineoplastic protocols for glioblastoma (GBM). Nonetheless, GBM is a deep-seated intracranial tumor with a serious hypoxic microenvironment; thus, ensuring a sufficient light penetration depth and oxygen (O2) supply are crucial to achieving a positive therapeutic outcome against GBM using PDT. Herein, InN@In2S3 core–shell nanorods are designed to serve as novel and indispensable PDT agents for GBM treatment. Unlike other PDT agents, InN@In2S3 features wide and strong near-infrared absorption that may improve the penetration depth. Moreover, InN@In2S3 exhibits high electron–hole separation efficiency owing to its Ⅱ heterojunction. The separated holes catalyze the generation of O2 from H2O, thereby ensuring sufficient O2 supply for generating reactive oxygen species through a redox reaction between the generated O2 and separated electrons. Our study demonstrates an O2-free and penetration depth-unrestricted PDT strategy that will promote the clinical treatment of GBM with PDT.

Photodynamic Therapy-Induced Anti-Tumor Immunity: Influence Factors and Synergistic Enhancement Strategies.

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by activating photosensitizers (PSs) with light exposure to produce reactive oxygen species (ROS). Compared to traditional treatment strategies such as surgery, chemotherapy, and radiation therapy, PDT not only kills the primary tumors, but also effectively suppresses metastatic tumors by activating the immune response. However, the anti-tumor immune effects induced by PDT are influenced by several factors, including the localization of PSs in cells, PSs concentration, fluence rate of light, oxygen concentration, and the integrity of immune function. In this review, we systematically summarize the influence factors of anti-tumor immune effects mediated by PDT. Furthermore, an update on the combination of PDT and other immunotherapy strategies are provided. Finally, the future directions and challenges of anti-tumor immunity induced by PDT are discussed.