GBM (grade IV astrocytoma) is the most aggressive and life-threatening brain tumor among all human malignancies, characterized by its highly recurrent and invasive nature [[1], [2], [3]]. The yearly occurrence of GBM is approximately 5 cases per 100000 individuals, with a median survival time of only about 14.6 months [4]. Despite multi-disciplinary treatments (MDT) involving extensive surgical resection, oral administration of alkylating agent temozolomide (TMZ), and adjuvant radiotherapy, GBM patients still suffer from tumor recurrence within a mean time of around 32–36 weeks after the initial MDT [[5], [6], [7]]. One crucial factor lies in the presence of GBM stem cells (GSCs). These GSCs possess remarkable self-renewal capacity, tumorigenic potential, and cellular plasticity, which enable their survival under dynamic micro-environmental changes involving surgical intervention and chemotherapy, ultimately leading to tumor relapse [8,9].

Autophagy is an evolutionarily conserved degradative pathway that maintains intracellular catabolic stability in yeasts, plants, and mammals. It has been implicated in cell death and cytoprotection during GBM tumorigenesis and recently reported to be involved in stem/progenitor cell expansion and chemotherapy resistance in tumor recurrence [[10], [11], [12], [13]]. Autophagy can be characterized as the selective recycling of cellular components, such as damaged DNA, misfolded proteins, and dysfunctional organelles, through their delivery to the lysosomes for clearance to sustain energetic homeostasis [14,15]. Therefore, the normal integrity and function of lysosomes play crucial roles in the late stage of autophagic process. Recently, lysosomal damage or dysfunction has been linked to neurodegeneration in humans, and targeting lysosomes for LMP-induced cell death was reported as a strategy for cancer therapy [[16], [17], [18]]. In contrast, other research revealed that overexpression of LAMP2 could reverse stress-induced blockade of autophagic flux and subsequently alleviate LMP-induced lysosomal cell death [19]. Furthermore, the stability of autophagic flux has been implicated as a critical factor that affects GBM cells proliferation. Disturbance in autophagic flux such as extensive activation or impaired autolysosomes may have catastrophic consequences on cell fate [[20], [21], [22]]. Therefore, we presume that preserving lysosomal function may affect GBM tumorigenesis and recurrence by maintaining the stability of autophagic flux.

In our previous study, we investigated the correlation between autophagy-related genes (ATGs) and GBM prognosis at genome level by analyzing the mRNA sequencing data of six GBM and four control brain tissues. After cross-referencing with ATGs listed in the Human Autophagy Database, we identified 42 dysregulated mRNA transcripts, including MAPK1, LC3, BAX, and DRAM-1. These findings suggested their potential involvement in gliomagenesis through autophagy [23]. Notably, DRAM-1 is a p53 target gene that encodes a lysosomal protein responsible for inducing macro-autophagy and damage-induced programmed cell death. Analysis of DRAM-1 in primary tumors revealed frequent decreased expression [24]. Moreover, a recent study has identified the critical role of DRAM-1 in mTORC1 activation through facilitation of lysosomal amino acid efflux, thereby underscoring its importance in metabolic homeostasis and cell differentiation [25]. Geng et al. recently reported that DRAM-1 played a tumor suppressor role in non-small cell lung cancer cells by facilitating lysosomal degradation [26]. These findings suggest that DRAM-1 may regulate tumor cell proliferation by modulating lysosomal function and autophagic flux stability. In line with these concepts, we initiated a systematic survey into the alterations of DRAM-1 expression in GBM cells and explored their impact on lysosomal function and autophagic process. Additionally, we examined therapeutic strategies involving TMZ and autophagy modulators to target GBM growth both in vitro and in vivo.