biostudies-literatureLiu SNatural Science Foundation of Beijing MunicipalityNational Natural Science Foundation of ChinaBeijing Natural Science Foundation104075https://www.ebi.ac.uk/biostudies/studies/S-EPMC12907902biostudies-literatureUnknown91Inhibiting 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.Redox biologyPD-L1-targeted photodynamic therapy orchestrates checkpoint blockade and immunogenic cell death for synergistic cancer immunotherapy.PMC1290790282203788JQ220212217700822377005Yang ZLi ZWang BHuan SWei XLiu SLiu GfalsePD-L1-targeted photodynamic therapy orchestrates checkpoint blockade and immunogenic cell death for synergistic cancer immunotherapy.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.2026-01-01T00:00:00Z2026 Feb2026-07-09T10:16:01.703Z2026-07-09T10:14:01.083ZS-EPMC129079024166667810.1016/j.redox.2026.104075