The immune landscape in brain metastasis

Abstract

The prognosis for patients with brain metastasis remains dismal despite intensive therapy including surgical resection, radiotherapy, chemo-, targeted, and immunotherapy. Thus, there is a high medical need for new therapeutic options. Recent advances employing high-throughput and spatially resolved single-cell analyses have provided unprecedented insights into the composition and phenotypes of the diverse immune cells in the metastatic brain, revealing a unique immune landscape starkly different from that of primary brain tumors or other metastatic sites. This review summarizes the current evidence on the composition and phenotypes of the most prominent immune cells in the brain metastatic niche, along with their dynamic interactions with metastatic tumor cells and each other. As the most abundant immune cell types in this niche, we explore in detail the phenotypic heterogeneity and functional plasticity of tumor-associated macrophages, including both resident microglia and monocyte-derived macrophages, as well as the T-cell compartment. We also review preclinical and clinical trials evaluating the therapeutic potential of targeting the immune microenvironment in brain metastasis. Given the substantial evidence highlighting a significant role of the immune microenvironmental niche in brain metastasis pathogenesis, a comprehensive understanding of the key molecular and cellular factors within this niche holds great promise for developing novel therapeutic approaches as well as innovative combinatory treatment strategies for brain metastasis.

Keywords: brain metastasis; combination therapy; immune microenvironment; metastatic niche.

Figure 1.

Simplified overview of tumor–immune interactions in the brain metastatic microenvironment. This figure illustrates the well-established (consensus) interactions between various immune cell subsets and metastatic tumor cells, providing an overview of the immune dynamics in brain metastasis. Arrows indicate supportive interactions, inhibitory arcs indicate inhibition, and dotted lines suggest interactions with only limited evidence. Myeloid and lymphatic immune cell populations reveal dynamic interactions with tumor cells in the metastatic microenvironment, impacting treatment response, recurrence, and patient survival. Beyond, cellular intrinsic factors such as tumor genotype and immune cell ontogeny, as well as extrinsic ones such as patient demographics and pretreatment, shape the observed immune cell phenotypes.

Figure 2.

Functional contribution of TAMs along the metastasis cascade. Microglia contribute to the establishment of the premetastatic niche and aid tumor cell extravasation by altering the BBB. During early metastatic establishment, microglia are reprogrammed by tumor-derived signals to facilitate invasion and colonization. Monocytes attracted to the metastatic site differentiate into MDMs further aiding metastatic growth. Finally, in the surrounding of established metastases, TAMs attract lymphocytes and convey immunosuppression.