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Updated: Jan 12, 2026
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Mitochondria-targeted carbon monoxide delivery nanoplatform for enhanced cancer immunotherapy through
Chengbin Wang1, Xuan Cheng2, Jian Fang1
1Key Laboratory for Advanced Materials, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China.
Abstract:
Despite the clinical efficacy of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade therapy, suboptimal patient response rates and unresolved resistance mechanisms remain significant challenges. To address this, we developed a mitochondria-targeted carbon monoxide (CO)-delivering nanoplatform, MnCOTPP/ICG@Cu(tz)@HA (CMIH), designed to disrupt the PD-L1/PD-1 axis through CO-mediated PD-L1 downregulation, thereby augmenting antitumor immunity. The CMIH platform was engineered by co-encapsulating a mitochondria-localized CO donor (MnCOTPP) and the photosensitizer indocyanine green within copper-based metal-organic frameworks (Cu(tz)MOF), followed by hyaluronic acid surface modification for CD44-targeted tumor delivery. Under near-infrared irradiation, mitochondria-localized CO release selectively inhibits cytochrome c oxidase, impairing mitochondrial respiration and alleviating tumor hypoxia. This dual action amplifies singlet oxygen generation to potentiate oxidative stress and immunogenic cell death induction, while concurrently suppressing PD-L1 expression to block immune evasion and reprogram the immunosuppressive tumor microenvironment. Mechanistically, CMIH orchestrates multimodal effects: (1) HIF-1α downregulation, (2) AMPK-mediated PD-L1 degradation, and (3) PD-L1/PD-1 axis blockade. In vivo studies demonstrate that CMIH robustly activates AMPK while suppressing HIF-1α and PD-L1 expression, eliciting potent antitumor immunity and metastasis inhibition. This study introduces a novel CO-based nanotherapeutic strategy that synergistically targets metabolic reprogramming and immune checkpoint blockade, offering a promising solution to overcome current limitations in cancer immunotherapy.
Insights
This study introduces a novel carbon monoxide-releasing nanoplatform that targets mitochondria to downregulate PD-L1 expression, enhancing antitumor immunity and overcoming resistance to cancer immunotherapy.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade therapy shows clinical efficacy but faces challenges with patient response rates and resistance.
- Current immunotherapies require novel strategies to overcome tumor microenvironment-mediated immune suppression.
Purpose of the Study:
- To develop a mitochondria-targeted, carbon monoxide (CO)-delivering nanoplatform (CMIH) to disrupt the PD-L1/PD-1 axis.
- To enhance antitumor immunity and overcome resistance in cancer immunotherapy.
Main Methods:
- Engineered a nanoplatform (CMIH) by co-encapsulating a CO donor (MnCOTPP) and indocyanine green within copper-based metal-organic frameworks, with hyaluronic acid surface modification.
- Utilized near-infrared irradiation to trigger mitochondria-localized CO release, inhibiting cytochrome c oxidase, alleviating tumor hypoxia, and generating singlet oxygen.
- Investigated CMIH's mechanism involving HIF-1α downregulation, AMPK-mediated PD-L1 degradation, and PD-L1/PD-1 axis blockade.
Main Results:
- CMIH effectively inhibited cytochrome c oxidase, reduced tumor hypoxia, and induced oxidative stress and immunogenic cell death.
- In vivo studies showed CMIH activated AMPK, suppressed HIF-1α and PD-L1 expression, and inhibited tumor growth and metastasis.
- The nanoplatform demonstrated potent antitumor immunity by reprogramming the immunosuppressive tumor microenvironment.
Conclusions:
- The developed CO-based nanotherapeutic strategy synergistically targets metabolic reprogramming and immune checkpoint blockade.
- CMIH offers a promising approach to address limitations in current cancer immunotherapy, improving patient response rates and overcoming resistance mechanisms.
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