New strategies to enhance photodynamic therapy for solid tumors

New strategies to enhance photodynamic therapy for solid tumors

The design of activatable photosensitizers and applications in precision immunomodulation.

As a non-invasive and spatiotemporally controllable therapeutic strategy, photodynamic therapy (PDT) exhibits distinct advantages in cancer treatment. However, conventional photosensitizers often trigger off-target toxicity due to insufficient tumor-targeting ability, and their uncontrollable activation at non-lesion sites severely compromises therapeutic precision and immunomodulatory potential. Activatable photosensitizers achieve site-specific activation by responding to endogenous tumor signals or exogenous physical stimuli, enabling the selective generation of reactive oxygen species (ROS) in tumor tissues. ROS generated not only induce tumor cell apoptosis but also modulate the immune system through multiple pathways, including the induction of immunogenic cell death (ICD), activation of the stimulator of interferon genes (STING) pathway, and remodeling of the immunosuppressive tumor microenvironment. This review systematically elaborates on the molecular design principles of activatable photosensitizers and their recent advances in precise immunomodulation for cancer therapy. From the perspective of molecular design, we focus on smart responsive systems that target tumor endogenous signals (e.g., enzymes, ROS, pH, glutathione) and exogenous physical stimuli (e.g., light, ultrasound, X-ray), aiming to enhance the specific activation and accumulation of photosensitizers in tumor sites. In terms of immunomodulation, we delve into the underlying mechanisms by which activatable photosensitizers synergistically potentiate anti-tumor immune responses. Finally, we discuss current challenges, such as tumor microenvironment heterogeneity and inadequate deep tissue penetration, while outlining future directions, including multi-stimuli synergistic activation, structural optimization, and mechanistic elucidation. This review aims to provide valuable insights for advancing activatable photosensitizer-mediated precision immuno-oncology.

Photodynamic Therapy in Cancer: Mechanisms, Photosensitizer Technology, Vitamin Modulation, and Rational Combination Design

Overall, PDT combination design should be guided by whether adjunctive agents support or undermine photosensitizer accumulation, oxygen availability, ROS-mediated cytotoxicity, and immune activation, when selected according to mechanistic compatibility.

Curcumin as a natural photosensitizer in photodynamic therapy: efficacy against metastatic melanoma cells.

Malignant melanoma is one of the most aggressive and lethal forms of skin cancer, posing a significant global health challenge. Despite therapeutic advances, current treatment strategies remain limited in efficacy, highlighting the need for alternative approaches. Photodynamic therapy (PDT) is a minimally invasive treatment that uses a photosensitizer activated by specific light wavelengths to generate reactive oxygen species (ROS), leading to targeted destruction of cancer cells. Curcumin, a natural phenolic compound derived from Curcuma longa, possesses diverse pharmacological properties, including anticancer activity, and has emerged as a potential photosensitizer. This study aimed to evaluate the in vitro efficacy of curcumin-mediated PDT in inducing cytotoxic effects in metastatic melanoma (A375) cells. A375 cells were treated with curcumin followed by irradiation using a 405 nm laser at fluence levels of 5 and 15 J/cm². Post-irradiation incubation was conducted for 24 and 48 h. Cellular responses were assessed via ROS detection assays, nuclear damage evaluation (using nuclear staining), apoptosis assays, morphological observation, and cell viability tests. Curcumin-PDT treatment induced a fluence- and time-dependent increase in intracellular ROS levels. Treated cells exhibited marked nuclear fragmentation, reduced viability, morphological alterations, and significant apoptosis compared to control groups. The extent of these effects correlated with both laser fluence and incubation time. These findings confirm that curcumin, upon photoactivation, induces oxidative stress and apoptosis in melanoma cells, thereby reducing cell survival. These results support the potential of curcumin as a natural photosensitizer in PDT and suggest its promising application in nanobioconjugate delivery systems for melanoma therapy.

Combination of 5-Aminolevulinic Acid and Indocyanine Green in Photodynamic Therapy for Squamous Cell Carcinoma: An In Vivo Study

Photodynamic therapy (PDT) is a promising minimally invasive treatment for non-melanoma skin cancer (NMSC). Still, its clinical efficacy is limited by light attenuation and drug distribution within tumor tissue, which restricts photosensitizer activation in deeper tumor regions. PDT with 5-aminolevulinic acid (ALA) is widely used as a precursor to induce accumulation of protoporphyrin IX (PpIX), followed by red light irradiation; it is effective for superficial lesions but often fails to achieve complete tumor control in thicker tumors, contributing to long-term lesion recurrence. To address this limitation, we investigated a two-photosensitizer, two-wavelength-PDT approach that combines ALA with indocyanine green (ICG), a near-infrared (NIR)-responsive photosensitizer that can be activated at greater tissue depths. This also promotes different cellular death targets, since ALA-mediated PDT mainly induces direct tumor cell killing through apoptosis and necrosis, whereas ICG-mediated PDT may contribute to treatment effects. In this study, a preclinical model of cutaneous squamous cell carcinoma (SCC) was used, with animals assigned to control, single-photosensitizer PDT (ALA, ICG), and combined photosensitizer PDT treatment groups. The effect of photosensitizer administration and light irradiation sequence on therapeutic efficacy was also investigated, and tumor progression and survival outcomes were monitored over time. The results indicated that the combined ALA+ICG-PDT approach produced the most sustained suppression of tumor growth and significantly prolonged animal survival compared with single-photosensitizer PDT. Importantly, these findings demonstrated a strong dependence on the sequence in which the photosensitizer and light are applied. These findings indicate that integrating photosensitizers activated at complementary wavelengths may improve treatment coverage across the tumor and partially overcome depth-related limitations associated with PDT, representing a promising strategy to enhance PDT efficacy for NMSC and other solid tumors.

Complementary cytotoxicity of GD2-targeted photoimmunotherapy and 5-aminolevulinic acid photodynamic therapy in neuroblastoma and osteosarcoma