Harnessing immunotherapy for brain metastases: insights into tumor–brain microenvironment interactions and emerging treatment modalities

Abstract

Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies, with a median survival timeframe nearing six months. Existing therapeutic regimens yield suboptimal outcomes; however, burgeoning insights into the tumor microenvironment, particularly the immunosuppressive milieu engendered by tumor–brain interplay, posit immunotherapy as a promising avenue for ameliorating brain metastases. In this review, we meticulously delineate the research advancements concerning the microenvironment of brain metastases, striving to elucidate the panorama of their onset and evolution. We encapsulate three emergent immunotherapeutic strategies, namely immune checkpoint inhibition, chimeric antigen receptor (CAR) T cell transplantation and glial cell-targeted immunoenhancement. We underscore the imperative of aligning immunotherapy development with in-depth understanding of the tumor microenvironment and engendering innovative delivery platforms. Moreover, the integration with established or avant-garde physical methodologies and localized applications warrants consideration in the prevailing therapeutic schema.

Environment-responsive dendrobium polysaccharide hydrogel embedding manganese microsphere as a post-operative adjuvant to boost cascaded immune cycle against melanoma

“…Melanoma accounts for the third prevalent cause of brain metastasis and the progression to brain metastasis leads to poor prognosis 38 . Activated T cells can migrate to the brain and induce antitumor responses 39 , 40 , providing a potential strategy for inhibiting brain tumors. Following the same post-operative adjuvant procedures of the primary model of melanoma, a secondary tumor was inoculated by intracranial injection of luciferase-expressing B16-F10 cells (Figure 6 A).…”

PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cells in lung cancer brain metastasis.

“…These factors collectively contribute to impeding the effectiveness of CAR T-cells in CNS tumors. [47][48][49] By utilizing repetitive in vivo TPLSM we are capable of elucidating intratumoral CAR T-cell dynamics from early stages of tumor formation until late timepoints, when large tumors have formed. After intracerebral injection of CAR T-cells, we initially observed higher intratumoral densities of EpCAM-directed CAR T-cells compared to undirected CAR T-cells.…”

Case report: Immunotherapy guided by molecular profiling of tumors: illustrative cases and literature review

“…However, several studies have also shown the benefit of pembrolizumab administration in these patients ( 19 , 20 ). Pembrolizumab has demonstrated efficacy in treating a variety of cancer types, including melanoma and non-small cell lung cancer, and there have been promising results in patients with brain metastases ( 19 , 21 ). In addition, ongoing research is focused on exploring ways to improve the response of brain metastases to ICIs, such as combining treatment with other therapies or optimizing dosing regimens ( 19 , 22 ).…”