2. Academic Validation
  3. Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy

Reprogramming of cancer metabolism via photoresponsive nano-PROTAC enhances pyroptosis-mediated immunotherapy

  • Signal Transduct Target Ther. 2025 Sep 26;10(1):310. doi: 10.1038/s41392-025-02405-6.
Byeongmin Park # 1 2,  Jiwoong Choi # 1 3,  Jae-Hyeon Lee # 4,  Yelee Kim 1,  Woohyeong Lee 1,  Ansoo Lee 1 5,  In-Cheol Sun 1,  Hong Yeol Yoon 1,  Yongju Kim 2,  Sun Hwa Kim 1 2,  Yoosoo Yang 6,  Kwangmeyung Kim 7 8,  Jooho Park 9,  Man Kyu Shim 10 11
Affiliations

Affiliations

  • 1 Biomedical Research Division, Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 2 KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
  • 3 Department of Immunology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
  • 4 BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea.
  • 5 Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea.
  • 6 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
  • 7 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
  • 8 Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, Republic of Korea.
  • 9 BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea. pkjhdn@kku.ac.kr.
  • 10 Biomedical Research Division, Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea. mks@kist.re.kr.
  • 11 Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea. mks@kist.re.kr.
  • # Contributed equally.
PMID: 40998785 DOI: 10.1038/s41392-025-02405-6
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.

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