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

Context-Dependent Mechanisms of Oncologic Photodynamic Therapy: A Framework Linking Treatment Parameters to Cellular, Vascular, and Immune Responses

Photodynamic therapy (PDT) combines a photosensitizer (PS), light, and molecular oxygen to generate cytotoxic reactive species, but nominally similar regimens can produce different biological responses because prescribed inputs do not directly specify the biologically active exposure state. Here, this intermediate state is treated as a multidimensional profile defined by PS localization and photoactive availability, the intratissue light field, oxygen dynamics, and vascular conditions at illumination. The relative contributions of direct tumor-cell injury, vascular damage, inflammatory signaling, and adaptive immune modulation also depend on drug–light interval (DLI), treatment sequence, vascular architecture, and tumor–host context. This critical narrative review applies a parameter–exposure state–mechanism–endpoint framework to oncologic PDT. It distinguishes spatially restricted primary photochemical injury from downstream multicellular effects and appraises the evidentiary thresholds for immunogenic cell death (ICD) and systemic immune claims. It also proposes reporting considerations and translational priorities to improve study comparability. PDT mechanisms should be interpreted against measurable treatment parameters rather than presumed from a PS label or prescribed dose alone.

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.

New strategies to enhance photodynamic therapy for solid tumors

Insights Into Natural Photosensitizer‐Based Nanotherapeutics in Photodynamic Therapy of Cancer

This review highlights mechanisms, recent advances, and translational challenges of natural PS‐based nanotherapeutics across multiple cancers, emphasizing strategies to improve delivery, selectivity, and therapeutic outcomes for next‐generation PDT.

Nanosystem-Mediated Phototherapy (PDT/PTT) - Chemodynamic Therapy for Synergistic Antitumor Therapy: Strategies and Advances

This review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition, and the key bottlenecks hindering clinical translation.

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.