Dichloroacetic Acid Enhances Photodynamic Therapy-Induced Regulated Cell Death in PANC-1 Pancreatic Cancer Cell Line.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late-stage diagnosis, dense stromal barriers, and resistance to conventional therapies. The tumor microenvironment (TME), marked by hypoxia, aberrant vasculature, and metabolic reprogramming, supports tumor persistence and immune evasion. Targeting metabolic and oxidative vulnerabilities in the TME offers a promising strategy to improve treatment outcomes. This study evaluated the combined effects of photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA), a precursor to the natural photosensitizer protoporphyrin IX (PpIX), and dichloroacetic acid (DCA), a mitochondrial function modulator, in the KRAS-mutated PANC-1 pancreatic cancer cell line. The combination of 5-ALA-PDT and DCA significantly reduced cell viability compared with either treatment alone. Mechanistic analyses revealed activation of multiple regulated cell death pathways, including mitochondria-mediated apoptosis, immunogenic cell death (ICD), and ferroptosis. This was evidenced by increased reactive oxygen species (ROS), loss of mitochondrial membrane potential (ΔΨm), release of danger-associated molecular patterns (DAMPs) such as ATP, and lipid peroxidation. DCA amplified PDT-induced oxidative stress, overcoming redox defenses and enhancing ferroptotic and immunogenic responses. These findings suggest that combining DCA with PDT enhances multimodal cell death in PDAC, providing a rationale for further in vivo studies to validate this redox-metabolic approach to treating chemoresistant pancreatic tumors.