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.