Phototherapy in cancer treatment: strategies and challenges

Abstract

Phototherapy has emerged as a promising modality in cancer treatment, garnering considerable attention for its minimal side effects, exceptional spatial selectivity, and optimal preservation of normal tissue function. This innovative approach primarily encompasses three distinct paradigms: Photodynamic Therapy (PDT), Photothermal Therapy (PTT), and Photoimmunotherapy (PIT). Each of these modalities exerts its antitumor effects through unique mechanisms-specifically, the generation of reactive oxygen species (ROS), heat, and immune responses, respectively. However, significant challenges impede the advancement and clinical application of phototherapy. These include inadequate ROS production rates, subpar photothermal conversion efficiency, difficulties in tumor targeting, and unfavorable physicochemical properties inherent to traditional phototherapeutic agents (PTs). Additionally, the hypoxic microenvironment typical of tumors complicates therapeutic efficacy due to limited agent penetration in deep-seated lesions. To address these limitations, ongoing research is fervently exploring innovative solutions. The unique advantages offered by nano-PTs and nanocarrier systems aim to enhance traditional approaches' effectiveness. Strategies such as generating oxygen in situ within tumors or inhibiting mitochondrial respiration while targeting the HIF-1α pathway may alleviate tumor hypoxia. Moreover, utilizing self-luminescent materials, near-infrared excitation sources, non-photoactivated sensitizers, and wireless light delivery systems can improve light penetration. Furthermore, integrating immunoadjuvants and modulating immunosuppressive cell populations while deploying immune checkpoint inhibitors holds promise for enhancing immunogenic cell death through PIT. This review seeks to elucidate the fundamental principles and biological implications of phototherapy while discussing dominant mechanisms and advanced strategies designed to overcome existing challenges-ultimately illuminating pathways for future research aimed at amplifying this intervention's therapeutic efficacy.

Fig. 1

Schematic illustration of PDT, PTT, and PIT including Jablonski diagram, Type-I and Type-II mechanism of PDT, and ICD and reversal of TME in PIT. The interaction between incident photons and chromophores leads to an electron in the ground state (S0) being excited to a transient high-energy singlet state (S1). Subsequently, the electron in the excited S1 state undergoes intersystem crossing (ISC), forming a more stable and longer-lived triplet state (T1). This T1 state interacts with various substances through Type I and Type-II pathways, generating reactive oxygen species (ROS), which is the principle of PDT. Internal conversion (IC), the primary mechanism of PTT, involves the electron in the S1 state relaxing non-radiatively back to S0, releasing part of its energy as heat, causing a sharp increase in local tumor temperature. Both PDT and PTT can initiate an antitumor immune response via the mechanism of ICD. This process involves the release of a series of danger-associated molecular patterns (DAMPs) and cytokines, promoting the recruitment and maturation of APCs, cross-presentation, and phagocytosis. The tumor antigens are then presented to T cells, ultimately activating the antitumor immune response. This is the main mechanism of PIT. PTT photothermal therapy. PDT photodynamic therapy. PIT photoimmunotherapy. ICD immunogenic cell death. iDC immature dendritic cell. mDC mature dendritic cell. M1 type 1 macrophages. M2 type 2 macrophages. NKT2 naturalkiller T. MDSC myeloid-derived suppressor cells. NK1 natural killer 1. The figure was created with BioRender.com

Fig. 2

Scheme of the biological effects of phototherapy. a Major mechanisms of PDT and PTT-induced regulated cell death modalities, including apoptosis, pyroptosis, necroptosis, ferroptosis, and cuproptosis. b PDT and PTT affect the vascular system during the process. Low-dose or short-duration PTT can transiently increase blood flow and oxygenation levels within tumors, thereby enhancing the antitumor efficacy of PDT. However, high-intensity or prolonged PTT can cause thermal damage and collapse of the tumor vasculature, reducing blood perfusion and oxygen saturation within the tumor, which may diminish the therapeutic effects of PDT. PDT induces vasoconstriction, vascular damage, and inhibition of tumor angiogenesis through the release of various vasoactive compounds. This vascular damage can exacerbate tumor hypoxia, further reducing the efficacy of PDT. RCD regulated cell death. MOMP mitochondrial outer membrane permeabilization. LPO lipid peroxidation. The figure was created with BioRender.com

Fig. 3

The timeline of photosensitizers used in PDT for cancer treatment. The timeline encompassing first-generation and second-generation PSs, as well as those currently under clinical trials. HpD hematoporphyrin derivative. mTHPC temoporfin. ALA 5-Aminolevulinic acid. AK actinic keratosis. BCC basal cell carcinoma. VTP vascular-targeted PDT. HPPH photochlor. The figure was created with BioRender.com

Fig. 4

Classification of seven different types of nano-phototherapeutic agents, specific examples, and their corresponding mechanisms of action illustrated. LSPR localized surface plasmon resonance. CB conduction band. VB valence band. QD quantum dot. LUMO lowest unoccupied molecular orbital. HOMO highest occupied molecular orbital. PDT photodynamic therapy. ACQ aggregation-caused quenching. AIE aggregation-induced emission. RIR restriction of intramolecular rotation. RIV restriction of intramolecular vibrations. The figure was created with BioRender.com

Fig. 5

Overview of several strategies for overcoming hypoxia limitations. a Overview of Decomposition of H₂O₂ to O₂ and Splitting water to O₂ within the tumor. b Mechanisms of inhibition of tumor mitochondrial oxidative phosphorylation. c Overview of HIF-1 pathway under normal and hypoxia conditions in cellular. d Illustration of the chemical reactions and related biochemical effects in tumor cells induced by PDT + CDT. NADH nicotinamide adenine dinucleotide. NAD nicotinamide adenine dinucleotide. ADP adenosine diphosphate. ATP adenosine triphosphate. HIF-1 hypoxia-inducible factor-1α. PHD prolyl hydroxylase domain. pVHL von Hippel–Lindau. PDT photodynamic therapy. PS photosensitizers. CDT Chemodynamic therapy. GSH glutathione. GSSG oxidized glutathione. The figure was created with BioRender.com

Fig. 6

Penetration Comparison. Comparison of the penetration depth of various excitation modalities (a) and light penetration depth (b). NIR-1 Near-Infrared-I. NIR-II Near-Infrared-II. MW microwave. The figure was created with BioRender.com

Fig. 7

Illustration of the three main mechanisms of UCNPs. The blue, yellow, and red arrows represent the excitation, energy transfer, and emission processes, respectively. ESA, excited-state absorption. ETU, energy transfer upconversion. PA, Photon avalanche. The figure was created with BioRender.com

Fig. 8

The mechanisms that combined PDT and PTT synergistic. PDT can enhance the sensitivity of cancer cells to heat, while the local hyperthermia induced by PTT increases the cells’ susceptibility to PDT. Both PDT and PTT can increase the permeability of tumor vasculature, improving oxygen saturation within the tumor tissue and enhancing drug distribution. Additionally, both therapies reduce the density of collagen in the ECM of tumors, softening the ECM and allowing for more effective drug penetration into the tumor. PDT photodynamic therapy. PTT photothermal therapy. ROS reactive oxygen species. ATP adenosine triphosphate. ABCG2 ATP-binding cassette subfamily G member 2. HCP-1 heme carrier protein 1. HSP90 heat shock proteins 90. HIF-1, hypoxia-inducible factor-1. PARP, poly-ADP-ribose polymerase. PS, photosensitizers. ECM extracellular matrix. The figure was created with BioRender.com