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Signal Transduct. Target. Ther., 26 September 2025;10:310 (2025) | https://doi.org/10.1038/s41392-025-02405-6
Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy
Byeongmin Park1,2, Jiwoong Choi1,8, Jae-Hyeon Lee 3, Yelee Kim1, Woohyeong Lee1, Ansoo Lee1,4, In-Cheol Sun1, Hong Yeol Yoon1, Yongju Kim2, Sun Hwa Kim1,2, Yoosoo Yang5, Kwangmeyung Kim6,7, Jooho Park3 and Man Kyu Shim1,4
1Biomedical Research Division, Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea;
2KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;
3BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea;
4Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea;
5Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea;
6College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea,
7Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, Republic of Korea and
8Present address: Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Correspondence: Jooho Park or Man Kyu Shim
These authors contributed equally: Byeongmin Park, Jiwoong Choi, Jae-Hyeon Lee
1Biomedical Research Division, Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea;
2KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea;
3BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea;
4Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea;
5Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea;
6College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea,
7Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, Republic of Korea and
8Present address: Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Correspondence: Jooho Park or Man Kyu Shim
These authors contributed equally: Byeongmin Park, Jiwoong Choi, Jae-Hyeon Lee
Abstract
Photodynamic therapy (PDT) induces tumor cell pyroptosis, a form of programmed cell death that triggers antitumor immunity. However, high glucose metabolism and hypoxic conditions in the tumor microenvironment (TME) limit PDT efficiency and impair effector cell function. Here, we propose a cancer metabolic reprogramming-enabling photoresponsive nanoproteolysis-targeting chimera (Nano-PROTAC; NanoTAC), derived from the supramolecular self-assembly of drug conjugates that bridge a PROTAC targeting hexokinase II (HK2) and a photosensitizer via a biomarker-cleavable linker. In a triple-negative breast cancer (TNBC) model, NanoTAC initially silences PROTAC activity and accumulates in tumor regions, where it undergoes linker cleavage in response to enzymatic biomarkers. Upon photoirradiation, PDT-induced pyroptotic cell death promotes the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to drive the cancer-immunity cycle. Concurrently, targeted protein degradation (TPD) via PROTACs counteracts glucose and oxygen consumption in the TME, ultimately potentiating pyroptosis-mediated photoimmunotherapy. This combination therapy achieves a high rate of complete regression in primary TNBC and confers adaptive immunity to prevent metastasis and recurrence. Our study presents a rationally designed nanomedicine that integrates PDT and PROTACs, shedding light on strategies for more effective cancer immunotherapy.
논문정보
- Research article
- 2025년 09월 (BRIC 등록일 2025-09-26)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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