5-ALA-mediated PpIX Accumulation in the Tumor Microenvironment of Glioma and its Implications for 5-ALA-based Local Tumor Therapies: A Review of the Literature

5-Aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) accumulation is widely used for fluorescence-guided surgery in malignant glioma. Beyond its diagnostic role, PpIX exhibits photo-, sono-, and radiosensitizing properties that enable locally applied tumor therapies. For these modalities, the cellular and subcellular localization of PpIX is a critical determinant of therapeutic efficacy, as it defines the site of reactive oxygen species generation and subsequent biological effects. In this comprehensive literature review, the cellular and subcellular distribution of 5-ALA-induced PpIX in gliomas and their tumor microenvironment (TME) was assessed. Studies were identified through a structured MEDLINE search and evaluated for evidence of PpIX localization in neoplastic and non-neoplastic cellular components. Accumulating data indicate that PpIX localizes not only within malignant glioma cells but also across multiple cellular components of the TME. Advanced imaging, single-cell, and spatial transcriptomic analyses demonstrate PpIX fluorescence frequently aligns with immunosuppressive myeloid populations and infiltrative tumor regions. Subcellularly, PpIX localizes in mitochondria, lysosomal-autophagic compartments, and extracellular structures, in a cell type dependent manner. These distribution patterns provide a biological basis for the immunomodulatory, anti-angiogenic, and cytotoxic effects observed in studies of 5-ALA-mediated local therapies. While macroscopic fluorescence remains clinically valuable for fluorescence-guided resection, the biologically relevant microscopic distribution of PpIX supports the concept that PpIX-based therapies may target not only tumor cells but also immunosuppressive and stromal compartments. A refined understanding of PpIX localization is therefore central to optimizing non-surgical 5-ALA-based therapies and their integration into multimodal glioma treatment paradigms.