Zwitterionic Photosensitizer Triggers Photopyroptosis for Effective Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Photopyroptosis, a light-activated cell death, shows promise for cancer therapy but faces challenges in hypoxic tumors.
• Designing photosensitizers (PSs) for effective photopyroptosis under tumor hypoxia is crucial.
• Mitochondrial-targeted Type I photodynamic therapy (PDT) offers a potential strategy.

Purpose of the Study:

• To develop a zwitterionic nano-photosensitizer (PCBMA-TAPP) for enhanced photopyroptosis and immunotherapy in hypoxic tumors.
• To investigate the efficacy of tetra (4-aminophenyl) porphyrin (TAPP)-based PSs for mitochondrial targeting and pyroptosis induction.
• To evaluate the therapeutic potential of PCBMA-TAPP in preclinical cancer models.

Main Methods:

• Comparative evaluation of porphyrin-based PSs to identify TAPP as a lead candidate.
• Encapsulation of TAPP into redox-responsive poly (carboxybetaine methacrylate) (PCBMA) nanogels.
• In vitro assays assessing cell death, inflammasome activation, and dendritic cell maturation.
• In vivo studies in EMT6 tumor-bearing mice to evaluate tumor growth inhibition and immune response.

Main Results:

• TAPP demonstrated superior mitochondrial localization and superoxide anion generation, inducing potent pyroptosis.
• PCBMA-TAPP exhibited prolonged circulation, enhanced tumor accumulation, and preserved photodynamic activity.
• In vitro, PCBMA-TAPP triggered plasma membrane disruption, ATP/LDH release, and NLRP3 inflammasome activation.
• In vivo, PCBMA-TAPP achieved 84.9% tumor growth inhibition with increased CD8+, CD4+, and granzyme B infiltration, showing no systemic toxicity.

Conclusions:

• The developed PCBMA-TAPP nanoplatform effectively synergizes Type I PDT with pyroptosis-driven immune activation.
• This strategy shows significant potential for treating hypoxic tumors via enhanced immunotherapy.
• The findings present a clinically translatable approach for advancing cancer immunotherapy.