Cannabidiol as an Immunomodulatory Adjuvant to Photodynamic Therapy: A Perspective on Enhancing Antitumor Immunity

Photodynamic therapy (PDT) is a clinically approved, minimally invasive light-based treatment that generates reactive oxygen species (ROS) to induce localized tumor eradication. In addition to its direct cytotoxicity, PDT induces immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) and stimulating antitumor immune responses. However, the efficacy of PDT is limited by poor light penetration, tumor hypoxia, intratumoral heterogeneity, and an immunosuppressive tumor microenvironment (TME). Cannabidiol (CBD), a non-psychoactive phytocannabinoid isolated from Cannabis sativa , has diverse pharmacological properties, including direct anticancer effects, redox modulation, and immunomodulatory effects that can address these limitations. In this Perspective, we evaluate the mechanistic rationale for combining PDT and CBD as a strategy to enhance anticancer immunity, despite the current evidence being largely limited to a few in vitro studies. We highlight the immunogenic effects of PDT, the anticancer and immunomodulatory activities of CBD and the possible synergistic mechanisms such as enhanced ICD, dendritic cell activation, T-cell priming and modulation of the TME. Preclinical in vitro and in vivo studies supporting this combination therapy are critically investigated, and the emerging role of nanotechnology-based co-delivery is highlighted. We also compare the PDT-CBD approach with established immunomodulatory strategies and provide recommendations for future research to address current evidence gaps and support clinical translation. Finally, we highlight important safety considerations, existing challenges and future research avenues for clinical application. Overall, the PDT-CBD combination therapy emerges as a promising next-generation immunogenic anticancer approach that warrants further investigation.