Hexylaminolevulinic acid in precision medicine: A review of advances in drug delivery and combination therapeutics

• Hexylaminolevulinic acid (HAL) causes the accumulation of protoporphyrin IX (PpIX) in tumor cells within a hormonal microenvironment by upregulating coproporphyrinogen oxidase (CPOX) and protoporphyrinogen oxidase (PPOX) and inhibiting ferrochelatase (FECH). • HAL's superior lipophilicity and cellular uptake over ALA, leads to a more efficient and selective PpIX production. • HAL demonstrates efficacy in fluorescence-guided surgery and photodynamic therapy across various cancers and antimicrobial applications. • HAL-based strategies improve diagnostic precision and therapeutic outcomes, supporting its potential in precision medicine and combinational treatments. 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 thiol oxidation and redoxsensitive oxidative modifications 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 (