Galectin-1-Targeted Type-I/II Photosensitizers Activate the NF-κB Pathway to Enhance Immunity and Treat High-Risk HPV-Associated Cervical Lesions

Persistent infection with high-risk HPV in women can progress to cervical intraepithelial neoplasia and even cervical cancer. This study investigated the cytotoxic and immunomodulatory effects of the TBTCN-TDG photodynamic therapy (PDT) probe in treating HPV-associated cervical lesions. The TBTCN-TDG probe was designed by integrating a donor-acceptor-π-acceptor 1 (D-A-π-A1) structure (TBTCN) with TDG, a moiety targeting Galectin-1, and its targeting ability in HPV-positive SiHa cells was confirmed. The in vitro results demonstrated that TBTCN-TDG combined with light treatment significantly inhibited SiHa cell proliferation, increased apoptosis, and activated immune responses by stimulating dendritic cells, macrophages, and NK cells, through enhanced NF-κB pathway signaling. In vivo, this targeted photosensitizer exhibited substantial therapeutic effects under laser excitation, as evidenced by TUNEL staining, which showed increased apoptosis in lesions. Immune analysis indicated that TBTCN-TDG enhanced NK cell viability and elevated the levels of pro-inflammatory cytokines under laser excitation, such as TNF-α, IFN-γ, and IL-6, confirming immune response activation. In conclusion, the combination of TBTCN-TDG and PDT effectively targets cells infected with HPV, enhances immune responses, and suppresses HPV infection. This suggests a novel therapeutic strategy for photodynamic immunotherapy in patients with cervical high-risk HPV infections.