TME-targeted approaches of brain metastases and its clinical therapeutic evidence

Abstract

The tumor microenvironment (TME), which includes both cellular and non-cellular elements, is now recognized as one of the major regulators of the development of primary tumors, the metastasis of which occurs to specific organs, and the response to therapy. Development of immunotherapy and targeted therapies have increased knowledge of cancer-related inflammation Since the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB) limit immune cells from entering from the periphery, it has long been considered an immunological refuge. Thus, tumor cells that make their way "to the brain were believed to be protected from the body's normal mechanisms of monitoring and eliminating them. In this process, the microenvironment and tumor cells at different stages interact and depend on each other to form the basis of the evolution of tumor brain metastases. This paper focuses on the pathogenesis, microenvironmental changes, and new treatment methods of different types of brain metastases. Through the systematic review and summary from macro to micro, the occurrence and development rules and key driving factors of the disease are revealed, and the clinical precision medicine of brain metastases is comprehensively promoted. Recent research has shed light on the potential of TME-targeted and potential treatments for treating Brain metastases, and we'll use that knowledge to discuss the advantages and disadvantages of these approaches.

Keywords: brain metastases; central nervous system barrier; immunotherapy; molecular mechanism; tumor microenvironment.

Figure 1

The primary steps in the progression of brain parenchyma cancer cell colonization. Reproduced under common creative licenses from (48).

Figure 2

The microenvironment regulates transmission cascades. Cell types residing in the brain and those recruited from elsewhere in the body can have pro-tumor or anti-tumor effects on brain metastases depending on the cell type and the cancer stage. (1) Microglia-derived factors, such as proteases (e.g., Ctss, Mmp3, and Mmp9), Wnt regulating elements, and chemokines (e.g., Cxcl12), are implicated in facilitating tumor cell transmigration across the blood-brain barrier (BBB) and into the brain parenchyma. (2) However, astrocytes can prevent metastasis by inducing tumor cell death via soluble FASL. Serpin released by tumor cells can mitigate this effect by preventing the manufacture of active plasmin, which converts FasL to sFasL. Tumor cells die upon their initial contact with astrocytes, but continued contacts between the two cells, controlled by gap junctions, promote tumor cell proliferation and confer chemotherapy resistance. CGAS-STING activates IRF, which generates IFN and TNF when tumor cells and astrocytes exchange cGAMP. (4) Eliminating tumor cells, cytotoxic T cells are a crucial component of the adaptive immune system’s response against brain metastases. Tumor cells acquire neural markers that cause spherocytosis during brain colonization, allowing them to reside in glial niches. Reproduced under common creative licenses from (61).

Figure 3

shows the stages of brain metastasis. There are four primary actions in the BMS cascade: There are four stages that metastatic cells must pass through before they may establish themselves in the CNS: 1) separation from the primary tumor, 2) surviving in the bloodstream, 3) invading the brain parenchyma, and 4) surviving in the brain’s microenvironment. Reproduced under common creative licenses from (39).