Among phototheranostic techniques, photothermal therapy (PTT) stands out as a promising modality. PTT utilizes photothermal agents capable of absorbing specific wavelengths of light and converting them efficiently into heat, thereby raising temperatures locally to induce tumor cell death. A critical aspect of this approach lies in the tumor-targeting ability of photothermal agents, which allows selective ablation of malignant tissue while sparing normal cells. However, widespread clinical adoption of PTT has been hampered by several obstacles, chief among them the risk of overheating, which can cause collateral damage to surrounding healthy tissues, and the sometimes insufficient tumor eradication leading to relapse.

Addressing these challenges, a recent collaborative research effort led by Professor ZHANG Pengfei of the Shenzhen Institute of Advanced Technology (SIAT) and his international colleagues has introduced an innovative dual-laser photothermal therapy (DLPTT) strategy. Their work, published in the prestigious journal Proceedings of the National Academy of Sciences, pioneers the use of two wavelengths—808 nm and 1,064 nm—in a sequential treatment protocol designed to enhance tumor ablation while reducing adverse effects. This breakthrough leverages specially engineered near-infrared photothermal agents exhibiting aggregation-induced emission (AIE) properties, which bolster imaging clarity and photothermal conversion efficiency.

The DLPTT strategy unfolds in two carefully calibrated stages. Initially, the tumor site undergoes a brief, high-temperature exposure using an 808 nm laser for approximately two minutes, achieving local temperatures around 50 °C. This phase achieves a crucial biological effect: it induces DNA damage in tumor cells and suppresses the expression of heat shock protein 70 (HSP70), a molecular chaperone known to confer thermotolerance. By inhibiting HSP70, this step effectively dismantles a key cellular defense mechanism, rendering cancer cells more vulnerable to subsequent treatment.

Following this priming stage, the therapy transitions to a longer-duration 1,064 nm laser irradiation, maintained at a slightly lower temperature near 43 °C over 13 minutes. This gentler heating phase is optimized to ablate residual tumor cells without provoking excessive inflammation or thermal injury to adjacent healthy tissues. The sequential use of two laser wavelengths capitalizes on their distinct tissue penetration depths and absorption profiles, enabling precise modulation of the tumor microenvironment and maximizing treatment efficacy.

A hallmark of this DLPTT protocol is the integration of second near-infrared window (NIR-II) fluorescence imaging, combined with photoacoustic imaging techniques. NIR-II imaging offers profound advantages, including deeper tissue penetration and significantly reduced scattering, which together produce images with enhanced signal-to-noise ratios. This highly sensitive imaging modality facilitates real-time visualization of tumors, even in deep tissue contexts, allowing clinicians to accurately localize and monitor the response of malignant lesions throughout therapy. Photoacoustic imaging complements this by providing additional anatomical and functional information, enriching the precision of treatment guidance.

Preclinical validation of this approach was conducted using the 4T1 breast cancer mouse model, a well-established system that closely mimics aggressive human breast cancer behavior. The results demonstrated that DLPTT significantly suppressed tumor growth, outstripping conventional single-laser PTT approaches in both effectiveness and safety. Importantly, treated animals showed no marked side effects, with stable body weights and no evident toxicity, underscoring the biosafety profile of this dual-laser regimen.

Further in vivo studies confirmed that DLPTT minimized systemic inflammatory responses, a common complication in thermal therapies. The reduction in inflammatory cytokine production suggests that the dual-laser strategy not only eradicates cancer cells but also preserves normal tissue homeostasis, which is vital for preventing adverse immune reactions and facilitating patient recovery.

Beyond its immediate therapeutic impact, this research also marks a significant advancement in the development of aggregation-induced emission (AIE) materials. AIE luminogens are a novel class of compounds whose fluorescence intensities increase upon aggregation, contrasting with conventional fluorophores that often suffer from quenching. Their use in photothermal agents enhances both imaging clarity and therapeutic precision, positioning them as versatile tools in the expanding field of phototheranostics.

Looking forward, the authors envision a promising future where DLPTT is integrated synergistically with immunotherapy. The combination of precise tumor ablation and immune system modulation could provide a powerful strategy to combat cancer metastasis and recurrence, addressing two of the most daunting challenges in oncology. By dismantling tumor cells locally and simultaneously activating systemic antitumor immunity, such combinatorial therapies hold the potential to redefine cancer care.

This groundbreaking study exemplifies the transformative potential of light-based technologies in modern medicine. By refining photothermal therapy through innovative laser strategies and advanced imaging, it paves the way for minimally invasive, highly effective cancer treatments that prioritize patient safety without compromising therapeutic potency. As research continues to evolve, phototheranostics promises to become a cornerstone of personalized oncology, offering hope for millions affected by breast cancer worldwide.

Subject of Research: Breast cancer photothermal therapy using dual-laser strategy and aggregation-induced emission materials

Article Title: Dual-laser “808 and 1,064 nm” strategy that circumvents the Achilles’ heel of photothermal therapy

News Publication Date: 9-Jun-2025

Web References:
https://doi.org/10.1073/pnas.2503574122

Keywords: Breast cancer, Photothermal therapy, Dual-laser strategy, Near-infrared imaging, Aggregation-induced emission, Phototheranostics, NIR-II fluorescence, Photoacoustic imaging, Tumor ablation, Heat shock protein, Immunotherapy integration

Photothermal therapy (PTT) stands out as a promising modality within phototheranostics. It utilises photothermal agents capable of converting absorbed light energy into heat, thereby inducing localized hyperthermia to ablate cancerous cells. Ideally, these agents should possess tumor-targeting abilities to maximize efficacy and reduce collateral damage. Yet, despite its appeal, PTT faces substantial translational hurdles. The delicate balance between generating sufficient heat to eradicate tumors and avoiding thermal injury to surrounding normal tissue remains challenging, and incomplete tumor ablation risks recurrence and metastasis.

A groundbreaking study published in the Proceedings of the National Academy of Sciences presents a novel dual-laser photothermal therapy (DLPTT) protocol designed to overcome the inherent limitations of conventional PTT. This interdisciplinary effort, led by ZHANG Pengfei at the Shenzhen Institute of Advanced Technology and conducted in collaboration with researchers from Korea University, the University of Texas at Austin, and Nanjing University of Posts and Telecommunications, introduces a two-step laser irradiation strategy that dramatically enhances therapeutic precision and efficacy.

The innovation rests upon the use of near-infrared (NIR) photothermal agents with aggregation-induced emission properties, which enable both superior tumor targeting and advanced imaging capabilities. In this context, the DLPTT method employs two distinct laser wavelengths sequentially, each optimized for specific therapeutic milestones. The initial phase involves a short 808 nm laser exposure lasting two minutes, calibrated to raise tumor temperatures to approximately 50°C. This step induces DNA damage and crucially suppresses the expression of heat shock protein 70 (HSP70), a molecular chaperone known to confer heat resistance to tumor cells.

By dampening HSP70 activity, the DLPTT approach effectively sensitizes cancer cells to subsequent thermal stress, addressing one of the principal biological hurdles that have limited PTT efficacy. The second phase applies a longer treatment with a 1,064 nm laser, extending over 13 minutes with tissue temperatures maintained around 43°C. This carefully controlled heating facilitates the ablation of residual tumor cells while minimizing inflammatory responses that often accompany aggressive thermal therapies. The two-stage process thus exploits the differential biological responses of tumor cells to heat, ensuring enhanced destruction of malignant tissue with reduced side effects.

Critical to the success of this approach is the integration of second near-infrared window (NIR-II) fluorescence imaging combined with photoacoustic imaging. NIR-II imaging benefits from deeper tissue penetration and reduced scattering compared to conventional imaging modalities, allowing for more precise localization of tumors deep within biological tissues. This dual-imaging modality provides dynamic, high signal-to-noise ratio images that guide the targeted laser irradiation, ensuring that therapeutic heat is confined to malignant tissues. In preclinical 4T1 breast cancer mouse models, this dual-imaging strategy demonstrated striking tumor growth inhibition without apparent systemic toxicity.

Comprehensive in vivo biosafety assessments further validated the clinical potential of DLPTT. Mice subjected to treatment exhibited stable body weight trajectories and minimal elevation of inflammatory cytokines, indicators of low systemic toxicity. These findings suggest that DLPTT achieves a high therapeutic index, effectively eradicating tumors while preserving overall physiological homeostasis. Maintaining biosafety is of paramount importance in any translational cancer therapy, and this study sets a precedent for combining effective tumor ablation with a favorable safety profile.

This dual-laser methodology also advances the field of aggregation-induced emission (AIE) materials, which have garnered increasing attention for their unique photophysical properties in biomedical applications. The use of AIE-active photothermal agents allows for enhanced light absorption, efficient heat generation, and superior imaging capacity, making them ideal candidates for integrated phototheranostic platforms. By harnessing these materials, the research team has demonstrated a scalable and versatile approach that could be adapted for a variety of solid tumors beyond breast cancer.

Looking forward, this pioneering work opens multiple avenues for future exploration and clinical translation. Of particular interest is the potential combination of DLPTT with immunotherapy agents, which could synergistically activate systemic anti-tumor immune responses while locally controlling primary tumors. Such integration holds promise for combatting tumor metastasis and recurrence, challenges that conventional therapies struggle to address effectively. The strategic enhancement of tumor ablation through DLPTT may prime the immune system for durable tumor suppression.

Moreover, the dual-laser strategy addresses the Achilles’ heel of traditional PTT by mitigating treatment resistance mechanisms and restricting thermal damage. This fine-tuned control over laser parameters and treatment timing exemplifies the growing sophistication in photomedical engineering. As laser technology continues to advance, future devices may incorporate adaptive feedback systems to further personalize therapy based on real-time imaging and thermal monitoring, pushing the boundaries of precision medicine.

In summary, the study from the Shenzhen Institute of Advanced Technology and collaborators represents a significant step forward in breast cancer phototheranostics. By combining dual-wavelength laser irradiation, cutting-edge NIR-II fluorescence and photoacoustic imaging techniques, and innovative photothermal agents, the DLPTT approach achieves highly effective tumor eradication with minimal side effects in preclinical models. This integrated method promises to transform the therapeutic landscape for breast cancer and sets a new benchmark for photothermal therapeutic strategies.

The implications of this research extend beyond breast cancer, suggesting a versatile platform adaptable to other malignancies requiring precise ablation. The successful clinical translation of DLPTT depends on further validation in larger animal models and eventual human trials, but the foundation laid by these findings is robust and inspiring. As research continues to optimize material properties, laser systems, and combinational therapies, phototheranostics may emerge as a cornerstone treatment modality in the era of personalized oncology.

Ultimately, this dual-laser photothermal therapy highlights the power of interdisciplinary collaboration across materials science, bioengineering, and clinical oncology. By merging fundamental scientific insights with practical therapeutic innovations, this study embodies the promise of next-generation cancer care—offering hope for more effective, safer, and less invasive treatment options that can significantly improve patient quality of life worldwide.

Subject of Research: Breast cancer phototheranostics, dual-laser photothermal therapy, aggregation-induced emission materials, near-infrared imaging.

Article Title: Dual-laser “808 and 1,064 nm” strategy that circumvents the Achilles’ heel of photothermal therapy

News Publication Date: 9-Jun-2025

Web References:
https://doi.org/10.1073/pnas.2503574122

References: Proceedings of the National Academy of Sciences, 2025.

Keywords: Breast cancer, photothermal therapy, dual-laser strategy, near-infrared imaging, aggregation-induced emission, tumor ablation, molecular heat shock protein suppression, phototheranostics, NIR-II fluorescence, photoacoustic imaging.