Photodynamic Therapy Innovations for Hypoxic Tumors

Photodynamic therapy (PDT) employs light-activated photosensitisers to generate cytotoxic reactive oxygen species (ROS) and achieve spatially precise cancer ablation. Traditional Type II PDT relies on energy transfer to molecular oxygen to produce singlet oxygen, but its efficacy is compromised in the hypoxic regions characteristic of solid tumours. To overcome this limitation, recent innovations have focused on oxygen-independent or oxygen-tolerant approaches. These include the design of Type I photosensitisers that generate superoxide and hydroxyl radicals via electron-transfer pathways, the development of tumour-activated catalytic systems that split water to yield ROS under red-light irradiation, and the conversion of conventional Type II agents into Type I mediators through in situ chemical transformations. Complementary strategies such as heavy-atom incorporation, supramolecular assembly and biotinylation further enhance radical production, minimise aggregation quenching and improve tumour selectivity. Collectively, these advances broaden the therapeutic window of PDT and lay the groundwork for more effective clinical applications in hypoxic tumour environments.

Research from Nature Portfolio

Recent studies have demonstrated polymer-based organic photosensitisers engineered for ultralow-power near-infrared excitation that can sensitize water to produce superoxide and hydroxyl radicals entirely under oxygen-free conditions. Another approach employs tumour-activated in situ synthesis of single-atom catalysts within the hypoxic microenvironment, enabling red-light-driven water splitting to generate hydroxyl radicals for precise tumour ablation without ambient oxygen. A third advance utilises naturally derived substrates converted into thymoquinone to act as efficient electron mediators, transforming classical Type II photosensitisers into Type I agents and markedly enhancing superoxide production under hypoxia. Together, these modular, tumour-responsive systems illustrate alternative photochemical pathways that effectively surmount the oxygen dependence of conventional PDT.

Photodynamic Therapy Innovations for Hypoxic Tumors publication trend

The graph below shows the total number of articles in photodynamic therapy innovations for hypoxic tumors across all publications each year (not limited to Nature Index journals).

Technical terms

Photodynamic therapy (PDT): A treatment combining a photosensitiser, light and a substrate (often oxygen) to produce cytotoxic species in situ.

Hypoxia: A condition of low oxygen concentration within tumour tissue that impairs oxygen-dependent therapies.

Reactive oxygen species (ROS): Highly reactive molecules—such as singlet oxygen, superoxide and hydroxyl radicals—that induce cellular damage.

Type I photosensitiser: A compound that generates ROS through electron-transfer mechanisms, producing radicals less dependent on molecular oxygen.

Type II photosensitiser: A compound that transfers energy to ground-state oxygen to form singlet oxygen, requiring sufficient oxygen availability.

References

1. Oxygen-independent organic photosensitizer with ultralow-power NIR photoexcitation for tumor-specific photodynamic therapy. Nature Communications (2024).
2. Selenium‐Containing Type‐I Organic Photosensitizers with Dual Reactive Oxygen Species of Superoxide and Hydroxyl Radicals as Switch‐Hitter for Photodynamic Therapy. Advanced Science (2023).
3. An unexpected strategy to alleviate hypoxia limitation of photodynamic therapy by biotinylation of photosensitizers. Nature Communications (2022).
4. Supramolecular photodynamic agents for simultaneous oxidation of NADH and generation of superoxide radical. Nature Communications (2022).
5. Tumor-activated in situ synthesis of single-atom catalysts for O2-independent photodynamic therapy based on water-splitting. Nature Communications (2024).
6. Thymoquinone as an electron transfer mediator to convert Type II photosensitizers to Type I photosensitizers. Nature Communications (2024).
7. Insights into the organic semiconducting photosensitizers for hypoxia-tolerant type I photodynamic therapy. Nano TransMed (2022).
8. Suppressing ACQ of molecular photosensitizers by distorting the conjugated-plane for enhanced tumor photodynamic therapy. Chemical Science (2024).