The Role of Bacteria in Central Nervous System Tumors: Opportunities and Challenges

Abstract

Tumors of the central nervous system (CNS) are severe and refractory diseases with poor prognosis, especially for patients with malignant glioblastoma and brain metastases. Currently, numerous studies have explored the potential role of bacteria and intestinal flora in tumor development and treatment. Bacteria can penetrate the blood-brain barrier (BBB), targeting the hypoxic microenvironment at the core of tumors, thereby eliminating tumors and activating both the innate and adaptive immune responses, rendering them promising therapeutic agents for CNS tumors. In addition, engineered bacteria and derivatives, such as bacterial membrane proteins and bacterial spores, can also be used as good candidate carriers for targeted drug delivery. Moreover, the intestinal flora can regulate CNS tumor metabolism and influence the immune microenvironment through the "gut-brain axis". Therefore, bacterial anti-tumor therapy, engineered bacterial targeted drug delivery, and intervention of the intestinal flora provide therapeutic modalities for the treatment of CNS tumors. In this paper, we performed a comprehensive review of the mechanisms and therapeutic practices of bacterial therapy for CNS tumors and discussed potential future research directions in this field.

Keywords: bacteria; central nervous system tumor; intestinal flora; targeted delivery; tumor microenvironment.

Figure 1

Photothermal immunotherapy of brain tumors mediated by attenuated bacteria: (a) bacteria form the Trojan Bacterial System by endocytosis of nanoparticles via the ABC transporter; (b) the Trojan Bacterial System crosses the BBB and targets brain tumors, where bacterial lysis triggers an immune response under exogenous near-infrared light irradiation. Reproduced with permission [11]. Copyright 2022, Springer Nature. Abbreviations: SiNP, silicon nanoparticle; GP, glucose polymer; ICG, indocyanine green; Trojan EC, Trojan Escherichia coli 25922; ABC, ATP-binding cassette; Trojan VNP, Trojan Salmonella typhimurium VNP20009; GBM, glioblastoma; BBB, blood–brain barrier; iDC, immature dendritic cell; mDC, mature dendritic cell; NK cells, natural killer cells.

Figure 2

Bacterial outer membrane protein-mediated targeted drug delivery. Targeting GRP94 using attenuated Escherichia coli DHα5 outer membrane proteins to target penetration of the BBB as well as access to the interior of brain metastases and carry EMB to induce apoptosis in tumor cells. Reproduced with permission [72]. Copyright 2023, Wiley-VCH. Abbreviations: E. coli, Escherichia coli; GRP94, glucose-regulated protein 94; BBB, blood–brain barrier; Omp@EMB, outer membrane protein-coated Embelin; NC core, nanocapsule core; L1CAM, cell adhesion molecule L1.

Figure 3

Targeted delivery of chemotherapeutic agents mediated by bacterial outer membrane proteins: (a) Neisseria meningitidis outer membrane protein Opca is combined with MnO₂-wrapped MTX to form a bionic nanotherapeutic system; (b) The bionic nanosystem crosses the BBB, targets brain tumors, and uses the catalytic effect of MnO₂ to alleviate the hypoxic environment inside the tumor and reverse the tumor’s resistance to MTX. Reproduced with permission [38]. Copyright 2022, Wiley-VCH. Abbreviations: MTX, methotrexate; MnO₂, manganese dioxide; Opca, outer membrane invasion protein; EDC/NHS, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide; BBB, blood–brain barrier; H₂O₂, hydrogen peroxide.