Hexylaminoacetylpropionic acid (HAL), a third-generation photosensitizer prodrug, exhibits targeted accumulation within tumor tissues and microbial biofilms. This review outlines advances in HAL-based drug delivery systems and their expanding use in various diseases, including oncology, antimicrobial therapy, and dermatologic diseases. Clinically, HAL has proven instrumental in enhancing diagnostic accuracy for bladder cancer by facilitating more complete surgical resections, while also demonstrating therapeutic efficacy against actinic keratosis and cervical intraepithelial neoplasia. These clinical advantages are complemented by novel nanocarrier systems that optimize drug delivery that improve patient tolerability. Recent findings point to an underappreciated the interplay between HAL-induced metabolic changes in tumours and anti-tumour immune responses, in which HAL-induced metabolic changes in tumours and anti-tumour immune responses, in which HAL-induced induces cell apoptosis through mitochondrial membrane permeabilization and the nuclear translocation of AIF, and enhances the efficacy of immune checkpoint blockade of key regulatory proteins reshape the tumour microenvironment and enhance immunogenicity. Thus, HAL is a candidate for combination with immune checkpoint inhibitors. However, challenges such as shallow light penetration (<2 mm) and the need for long-term safety validation limit its broader clinical utility. We propose three convergent strategies to address these limitations: (i) reactive oxygen species-responsive nanocarriers for targeted delivery in hypoxic environments, (ii) biomarker-guided combinatorial regimens, and (iii) data-driven treatment personalisation using patient-specific biomarkers. Together, these advances establish a translational framework for HAL as a platform in next-generation metabolism-targeted photomedicine.

Glioblastoma (GBM) remains clinically intractable owing to dismal prognosis and frequent recurrence. This study aimed to develop a dual-wavelength blue laser platform (450 nm and 405 nm) that integrates laser ablation, photodynamic diagnosis (PDD), and photodynamic therapy (PDT) in preclinical models, with 405 nm designated for PDD and 450 nm for PDT. Ex vivo ablation and coagulation were performed on porcine brain tissue using a 450 nm laser, compared with a conventional 980 nm laser or bipolar forceps. Subcutaneous and orthotopic GBM mouse models were used to assess 405 nm irradiation for tumor visualization following 5-aminolevulinic acid (5-ALA) administration. In vitro and in vivo experiments evaluated the therapeutic efficacy of 450 nm laser-mediated PDT, with 630 nm laser-mediated PDT serving as the positive control. Tumor recurrence was assessed after surgical resection combined with PDT. The 450 nm laser produced deeper and narrower incisions with less thermal coagulation than the 980 nm laser or bipolar forceps. 405 nm irradiation enabled clear tumor visualization, with peak 5-ALA-induced fluorescence at 2 h post-administration in subcutaneous tumors and 4 h in orthotopic tumors. The 450 nm laser induced concentration-dependent cytotoxicity in GBM cells and elicited robust photodynamic effects. Notably, surgical resection followed by PDT significantly suppressed tumor recurrence. These results validate an integrated strategy that uses a 405 nm laser for intraoperative PDD and a 450 nm laser for precise ablation and subsequent PDT, positioning this dual-wavelength blue laser platform as a promising, comprehensive approach to improving GBM surgical outcomes.