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Brain tumors are a malignant tumor of the nervous system that seriously endangers human health, among which the most common and most fatal is glioblastoma (glioblastoma multiforme, GBM). GBM is highly aggressive, recurrent and drug resistant, and current treatments include surgical resection, radiotherapy and chemotherapy, but its prognosis remains poor, with a median survival of only about 15 months. The occurrence and development of GBM is affected by its special metabolic and immune microenvironment (tumor microenvironment, TME), so the delivery and therapeutic strategies targeting GBM TME are of great significance and potential.

The metabolic features of GBM TME mainly include a high degree of glucose metabolism, oxidative stress, acidification, and hypoxia. These features allow GBM cells to adapt to a hostile environment, increasing growth factor signaling, antiapoptotic capacity, and genetic instability, while inhibiting immune cell function and penetration. Therefore, targeting the metabolic pathway of GBM TME is an effective therapeutic strategy to achieve anti-tumor effects by inhibiting the energy supply, increasing the oxidative pressure of tumor cells, improving the acid-base balance, or increasing the oxygen sensitivity of tumor cells.

For instance:

Inhibition of glucose transporter protein (glucose transporter, GLUT) or hexokinase (hexokinase, HK) can block glucose entry into tumor cells and participate in glycolysis, thus weakening the viability of tumor cells. A small molecule drug called 3-bromapidone (3-bromopyruvate, 3-BP), which inhibited both GLUT and HK, demonstrated potent anti-GBM activity in vitro and in vivo.

Inhibition of lactate dehydrogenase (lactate dehydrogenase, LDH) or monocarboxylate transporter (monocarboxylate transporter, MCT) blocks the release of lactate from tumor cells and leads to lactate accumulation and a pH decrease in tumor cells, thus inducing apoptosis of tumor cells. A small molecule drug called FX 11 inhibited LDH and showed anti-GBM activity in vitro and in vivo.

Inhibition of citrate synthase (citrate synthase, CS) or isocitrate dehydrogenase (isocitrate dehydrogenase, IDH) can block the development of citric acid cycle (tricarboxylic acid cycle, TCA cycle), and lead to the accumulation of citrate and decreased pH in tumor cells, thus inhibiting the proliferation and migration of tumor cells. A small molecule drug called BPTES suppresses CS and shows anti-GBM activity in vitro and in vivo.

Inhibition of glutamate decarboxylase (glutamate decarboxylase, GAD) or glutamate transporter (glutamate transporter, GLT) blocks the release of glutamate from tumor cells and leads to glutamate accumulation and pH decline in tumor cells, thus inhibiting the metabolism and signal transduction of tumor cells. A small molecule drug called DON suppresses GAD, showing anti-GBM activity in vitro and in vivo.