Multimodal phototherapy for Glioblastoma: from mechanistic action to synergistic delivery and therapeutic strategies

Abstract Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median overall survival of only 14–16 months despite maximal safe resection, radiotherapy, and temozolomide. The blood–brain barrier, infiltrative growth pattern, and tumor microenvironment-mediated therapeutic resistance severely limit the efficacy of conventional and emerging therapies. Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), offers spatially selective tumor ablation through light activation, minimal invasiveness, and the ability to trigger immunogenic cell death. Recent advances in second- and third-generation photosensitizers, near-infrared-absorbing photothermal agents, and multifunctional nanoplatforms have substantially improved tumor-specific accumulation and therapeutic indices in preclinical GBM models. Intranasal administration has emerged as a clinically attractive, noninvasive route to bypass the blood–brain barrier and deliver photosensitizers and photothermal agents directly to the brain. Preclinical studies have demonstrated that combining PDT or PTT with temozolomide, immune checkpoint inhibitors, or ferroptosis inducers yields synergistic antitumor effects, prolongs survival and abscopal responses, and reduces postsurgical recurrence in orthotopic GBM models. Despite these encouraging outcomes, clinical translation is currently hindered by the depth of light penetration in the human brain, the nonuniform distribution of the drug inside the tumor, and the lack of systematic light delivery methods. To date, few phase one clinical trials of PDT have been conducted, and the findings provide the possibility of PDT intervention to increase survival rates to a certain extent. This review critically tabulates and reports the principles and approaches for the translation of multimodal phototherapy for the treatment of glioblastoma. Graphical Abstract