Red light‐activated depletion of drug‐refractory glioblastoma stem cells and chemosensitization of an acquired‐resistant mesenchymal phenotype

Glioblastoma stem cells (GSCs) are potent tumor initiators resistant to radiochemotherapy, and this subpopulation is hypothesized to re‐populate the tumor milieu due to selection following conventional therapies. Here, we show that 5‐aminolevulinic acid (ALA) treatment—a pro‐fluorophore used for fluorescence‐guided cancer surgery—leads to elevated levels of fluorophore conversion in patient‐derived GSC cultures, and subsequent red light‐activation induces apoptosis in both intrinsically temozolomide chemotherapy‐sensitive and ‐resistant GSC phenotypes. Red light irradiation of ALA‐treated cultures also exhibits the ability to target mesenchymal GSCs (Mes–GSCs) with induced temozolomide resistance. Furthermore, sub‐lethal light doses restore Mes–GSC sensitivity to temozolomide, abrogating GSC‐acquired chemoresistance. These results suggest that ALA is not only useful for fluorescence‐guided glioblastoma tumor resection, but that it also facilitates a GSC drug‐resistance agnostic, red light‐activated modality to mop up the surgical margins and prime subsequent chemotherapy.