PD-L1-targeted photodynamic therapy orchestrates checkpoint blockade and immunogenic cell death for synergistic
Sijin Liu1, Zhaoting Yang2, Biao Wang3
1Beijing Key Laboratory of Medical-Engineering Integration and Translation for Malignant Tumors, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Abstract:
Inhibiting the PD1/PD-L1 interaction is crucial for developing novel cancer immunotherapies, particularly to reduce systemic toxicity and enhance patient response rates. In this study, we designed and synthesized Photodegradation-Targeting Chimeras (PDTACs) by conjugating a clinically approved photosensitizer, verteporfin, to a PD-L1-targeted peptide. Our optimized chimera, PPA-VPF, demonstrates a dual mechanism of action in cancer immunotherapy, resulting from singlet oxygen generated under light irradiation. The proximity-generated singlet oxygen effectively degrades PD-L1 in cancer cells through immediate protein breakdown and resulted in subsequent lysosomal-dependent degradation hours after irradiation. Additionally, the non-proximity-generated singlet oxygen induces immunogenic cell death (ICD) through cytotoxic effects. In mouse models with immune cold tumors, PPA-VPF elicited robust adaptive antitumor immunity and effectively inhibited the growth of both primary and distant tumors. This PD-L1-targeted PDTAC achieved immune checkpoint blockade and ICD induction in a single therapeutic mode using one molecular species, presenting a novel strategy for combinational immunotherapy, particularly in immune cold tumors.
Insights
This study introduces Photodegradation-Targeting Chimeras (PDTACs) for cancer immunotherapy. These novel agents target PD-L1, degrade it using light, and induce cancer cell death, enhancing immune response in tumors.
Area of Science:
- Oncology
- Immunotherapy
- Photodynamic Therapy
Background:
- Targeting the PD1/PD-L1 interaction is key for effective cancer immunotherapy.
- Reducing systemic toxicity and improving patient response rates are critical challenges in current treatments.
Purpose of the Study:
- To design and synthesize novel Photodegradation-Targeting Chimeras (PDTACs) for cancer immunotherapy.
- To evaluate the dual mechanism of action of a PDTAC conjugate (PPA-VPF) in degrading PD-L1 and inducing immunogenic cell death (ICD).
Main Methods:
- Conjugation of a photosensitizer (verteporfin) to a PD-L1-targeted peptide to create PDTACs.
- Assessment of PPA-VPF's dual mechanism: proximity-generated singlet oxygen for PD-L1 degradation and non-proximity singlet oxygen for ICD induction.
- Evaluation of PPA-VPF efficacy in mouse models of immune cold tumors.
Main Results:
- The optimized chimera PPA-VPF demonstrated effective degradation of PD-L1 in cancer cells via singlet oxygen.
- PPA-VPF induced both immediate protein breakdown and subsequent lysosomal-dependent degradation of PD-L1.
- Singlet oxygen also induced immunogenic cell death (ICD) and elicited robust adaptive antitumor immunity.
- Significant inhibition of primary and distant tumor growth was observed in mouse models.
Conclusions:
- PDTACs offer a novel single-molecule strategy for combinational immunotherapy, achieving immune checkpoint blockade and ICD induction.
- This approach is particularly promising for treating immune cold tumors.
- PPA-VPF presents a new therapeutic modality for enhancing cancer immunotherapy outcomes.
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