Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, poses a significant therapeutic challenge due to its highly invasive nature and resistance to conventional therapies, including surgery, chemotherapy, and radiotherapy. Despite advances in standard treatments, patient survival remains limited, requiring the exploration of innovative strategies. Photodynamic therapy (PDT) has emerged as a promising approach, leveraging light-sensitive photosensitizers (PSs), molecular oxygen, and specific light wavelengths to generate reactive oxygen species (ROS) that selectively induce tumor cell death. Originally developed for skin cancer, PDT has evolved to target more complex malignancies, including GBM. The refinement of second- and third-generation PS, coupled with advancements in nanotechnology, has significantly improved PDT’s selectivity, bioavailability, and therapeutic efficacy. Moreover, the combination of PDT with chemotherapy, targeted therapy, and immunotherapy, among other therapeutic modalities, has shown potential in enhancing therapeutic outcomes. This review provides a comprehensive analysis of the preclinical and clinical applications of PDT in GBM, detailing its mechanisms of action, the evolution of PS, and novel combinatory strategies that optimize treatment efficacy. However, several challenges remain, including overcoming GBM-associated hypoxia, enhancing PS delivery across the blood-brain barrier, and mitigating tumor resistance mechanisms. The integration of PDT with molecular and genetic insight, alongside cutting-edge nanotechnology-based delivery systems, may revolutionize GBM treatment, offering new prospects for improved patient survival and quality of life.

Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with limited therapeutic options and poor prognosis despite maximal surgery, radiotherapy, and chemotherapy. The complex and immunosuppressive tumor microenvironment, pronounced intratumoral heterogeneity, and the presence of the blood–brain barrier (BBB) severely restrict the efficacy of conventional and emerging therapies. In this context, cell-based strategies leveraging macrophages, mesenchymal stromal cells (MSCs), and their derivatives have gained attention as “cellular allies” capable of modulating the GBM microenvironment and acting as targeted delivery platforms. Methods: This review systematically analyzes preclinical and early clinical literature on macrophage- and MSC-based therapeutic strategies in GBM, including engineered cells, extracellular vesicles (EVs), membrane-coated nanoparticles, and hybrid biomimetic systems. Studies were selected based on relevance to GBM biology, delivery across or bypass of the BBB, microenvironmental modulation, and translational potential. Evidence from in vitro models, orthotopic and syngeneic in vivo models, and available clinical trials was critically evaluated, with emphasis on efficacy endpoints, biodistribution, safety, and manufacturing considerations. Results: The reviewed evidence demonstrates that macrophages and MSCs can function as active therapeutic agents or delivery vehicles, enabling localized oncolysis, immune reprogramming, stromal and vascular remodeling, and enhanced delivery of viral, genetic, and nanotherapeutic payloads. EVs and membrane-based biomimetic platforms further extend these capabilities while reducing cellular risks. However, therapeutic efficacy is highly context-dependent, influenced by tumor heterogeneity, BBB integrity, delivery route, and microenvironmental dynamics. Clinical translation remains limited, with most approaches at preclinical or early-phase clinical stages. Conclusions: Cell-based and cell-derived platforms represent a promising but still evolving therapeutic paradigm for GBM. Their successful translation will require rigorous biomarker-driven patient selection, improved models that capture invasive GBM biology, scalable GMP-compliant manufacturing, and rational combination strategies to overcome adaptive resistance mechanisms.