Immune response recalibration using immune therapy and biomimetic nano-therapy against high-grade gliomas and brain metastases

Abstract

Although with aggressive standards of care like surgical resection, chemotherapy, and radiation, high-grade gliomas (HGGs) and brain metastases (BM) treatment has remained challenging for more than two decades. However, technological advances in this field and immunotherapeutic strategies have revolutionized the treatment of HGGs and BM. Immunotherapies like immune checkpoint inhibitors, CAR-T targeting, oncolytic virus-based therapy, bispecific antibody treatment, and vaccination approaches, etc., are emerging as promising avenues offering new hope in refining patient's survival benefits. However, selective trafficking across the blood-brain barrier (BBB), immunosuppressive tumor microenvironment (TME), metabolic alteration, and tumor heterogeneity limit the therapeutic efficacy of immunotherapy for HGGs and BM. Furthermore, to address this concern, the NanoBioTechnology-based bioinspired delivery system has been gaining tremendous attention in recent years. With technological advances such as Trojan horse targeting and infusing/camouflaging nanoparticles surface with biological molecules/cells like immunocytes, erythrocytes, platelets, glioma cell lysate and/or integrating these strategies to get hybrid membrane for homotypic recognition. These biomimetic nanotherapy offers advantages over conventional nanoparticles, focusing on greater target specificity, increased circulation stability, higher active loading capacity, BBB permeability (inherent inflammatory chemotaxis of neutrophils), decreased immunogenicity, efficient metabolism-based combinatorial effects, and prevention of tumor recurrence by induction of immunological memory, etc. provide new age of improved immunotherapies outcomes against HGGs and BM. In this review, we emphasize on neuro-immunotherapy and the versatility of these biomimetic nano-delivery strategies for precise targeting of hard-to-treat and most lethal HGGs and BM. Moreover, the challenges impeding the clinical translatability of these approaches were addressed to unmet medical needs of brain cancers.

Keywords: Biomimetic nanoparticles; Blood-brain-barrier; Brain metastases; Clinical translatability; High-grade glioma; Immunotherapy.

Graphical abstract

Fig. 1

A detailed overview of the molecular signatures of HGG and their interaction with TME and highlights five distinct niche areas within GBMs. The hypoxic niche, characterized by PTEN and HIF upregulation, fosters tumor growth and resistance through VEGF and IL-8 upregulation, supporting stem cell presence marked by increased CD133. In the perivascular niche, angiogenesis and elevated VEGF levels accompany the accumulation of tumor macrophages and increased IL-6 and IL-8 cytokines, influenced by PTEN-mediated matrix proteins. The invasive niche facilitates tumor expansion into normal brain tissue, with GSCs associated with endothelial cells via CXCL12/CXCR4 signaling. The metabolic niche, driven by the Warburg effect, exhibits a metabolic shift towards aerobic glycolysis and lactate production, crucial for modulating the TME and promoting angiogenesis and immune evasion. Lastly, the stem cell niche supports GSCs' presence and maintenance, pivotal for tumor growth and resistance mechanisms.

Fig. 2

Schematic representation of the multifaceted process underlying BM. At its core, the figure delineates the journey of metastases-initiating cells (MICs) from primary tumor sites to colonization within the brain. MICs undergo crucial transitions, including EMT and mesenchymal-epithelial transition (MET), before adhering to the vascular endothelium and crossing the BBB. Subsequently, MICs interact with the brain microenvironment, navigating through a series of phases such as immune evasion, colonization, and growth, ultimately forming micro/macro metastases. Concurrently, the figure illustrates the pivotal role of polarized brain cells, notably astrocytes and microglia, in influencing BM progression. Astrocytes and microglia exhibit a dual role, contributing to both tumor promotion and inhibition, highlighting the complexity of the neuroinflammatory response. Moreover, the figure emphasizes the formation of a BM fortress characterized by immunosuppressive defenses and support from glial cells, culminating in a permissive environment for BM growth.

Fig. 3

Schematic illustration of the complex interplay between tumor cells, brain cells, and immune cells. Tumor cells manipulate various brain cells (such as microglia, astrocytes, pericytes, fibroblasts, and neurons etc.) to create an immunosuppressive microenvironment, hindering effector T-cell infiltration and promoting tumor progression. For instance, tumor cells induce mTOR-dependent regulation of STAT3 and NF-_KB activity in microglia and interact with pericytes to evoke their immunosuppressive function. Similarly, immune cells like Tregs, M2 macrophages, Breg, DCs, N2 neutrophils, and mast cells are manipulated to inhibit antitumor immune action, remodel the ECM, promote genetic instability, and support the outgrowth of early-stage tumors. This intricate interplay enables tumor cells to escape the immune system and proliferate.

Fig. 4

Current immunotherapy approach to treat HGGs and BM. Antibody therapy relies on DCs recognizing tumor lysates through the interaction of MHC class II T cell receptor (TCR) and CD80/86-CD28 (mainly used in the DC vaccine). DCs are effective in antigen presentation and can eliminate CTLs, which destroy glioma cells. Activation of CTL then targets and eliminates tumor cells containing glioblastoma-associated antigens (GAA) displayed on MHC class I molecules. However, tumor cells often avoid CTL destruction by activating immune ligands. For example, PD-L1 binds to PD-1 and inhibits lymphocyte activation. Blocking this interaction with monoclonal antibodies may prevent tumors from escaping. Similarly, blocking CTLA-4, an inhibitory immune molecule that blocks T cell activation by binding to CD80 and CD86, will promote dendritic growth through antibody-mediated blockade. GAAs, such as CD70, IL-13Rα2, and EGFRvIII, are present on the surface of tumor cells via MHC class I. These TAAs are genetically modified CARs-T targeting therapy. Additionally, genetic modification plays a role in the treatment of oncolytic disease by altering the virus to infect or replicate in tumor cells. Therefore, the destruction of tumor cells by these bacteria not only directly eliminates the virus but also causes immunogenic cell death. This activation may increase antigen presentation and stimulate the adaptive immune system against the tumor.

Fig. 5

The figure illustrates a dual-pronged approach to glioma therapy using advanced biomimetic drug delivery nanoplatforms. On the left, the sequential process of antigen-presenting dendritic cells (aDCs) is depicted, showcasing the activation by glioma cell lysates. The activated DCs then encapsulate BNPs loaded with therapeutic agents, forming aDCM@BNP complexes. On the right, a parallel mechanism is shown involving natural killer (NK) cells. Here, NK cells facilitate the encapsulation of BNPs containing anti-glioma drugs within a pegylated copolymer shell. The bottom section of the figure synergistically combines these two pathways, demonstrating their collective impact on the glioma TME. This dual approach not only targets the tumor cells but also modulates the surrounding stroma, leading to an amplified therapeutic effect against glioma.

Fig. 6

In this illustrative depiction, we observe the meticulous isolation of immunocytes, specifically neutrophils, from murine models. These cells are then ingeniously modified to encapsulate BNPs, a cutting-edge approach in targeted drug delivery. The figure highlights the strategic bio-surface modifications that enable these nanoparticles to traverse the formidable blood-brain and blood-brain-tumor barriers with remarkable specificity and selectivity. This innovative technique not only ensures the precise delivery of therapeutic agents to the glioma site but also significantly amplifies the suppression of glioma recurrence, marking a pivotal advancement in neuro-oncological therapeutics.

Fig. 7

The figure presents a comprehensive overview of the therapeutic potential of BNPs in HGG immunotherapy. In the top section, it illustrates the mechanism by which these nanoparticles facilitate the release of T cells from the bone marrow, effectively modulating the TMEto prevent T cell sequestration. The middle section delves into various immunotherapeutic nanoparticles designed to target the glioma TME, resulting in enhanced T cell infiltration, and heightened immune response. Finally, the bottom section depicts the strategic metabolic targeting by the BNPs, which disrupts the tumors metabolic pathways, thereby impeding its growth and survival.