Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8⁺ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy.

Background/Objectives: Immunotherapy has shown promising results in some cancers, but its efficacy remains limited in pancreatic ductal adenocarcinoma (PDAC). Vaccines in nanoparticle form (nanovaccines) can incorporate immunostimulating components to induce a potent immune response. As mesothelin (MSLN) is a tumor-associated antigen overexpressed in PDAC, we evaluated the effect of MSLN nanovaccine in a syngeneic orthotopic KPC-PDAC mouse model. Methods: An MSLN peptide combining three MSLN epitopes and two adjuvants, poly I:C and R848, was encapsulated in PLGA–chitosan nanoparticles to generate the nanovaccine. Results: The MSLN nanovaccine was successfully taken up by dendritic cells in vitro and was found in inguinal lymph nodes 24 h after subcutaneous injection into C57BL/6 mice. Nanovaccine re-stimulation of splenocytes from vaccinated mice led to increased levels of interferon-γ in vitro compared to unstimulated splenocytes. Higher levels of MSLN-specific IgM and IgG antibodies were detected in the serum of vaccinated mice compared to that of control mice. Three vaccination regimens were tested: a prophylactic scheme that included vaccination before tumor induction and two therapeutic schemes involving early and late vaccination after tumor cell inoculation. MSLN nanovaccination inhibited KPC tumor progression and metastasis and induced higher CD8⁺ T cell infiltration in the tumor that developed in response to prophylactic and early therapeutic schedules but not in response to a later vaccination approach. Although the nanovaccine treatment elicited higher humoral and cellular antigen-specific responses in tumor-bearing mice for both vaccination strategies, the therapeutic vaccination also increased the expression of exhaustion markers in CD8⁺ T cells. Conclusions: Our results support the relevance of an MSLN-based nanovaccine as a new immunotherapy treatment for PDAC and propose an innovative method of vaccine delivery using NPs.