From Design to Clinic: Engineered Nanobiomaterials for Immune Normalization Therapy of Cancer

Abstract

is actively involved in T cell exhaustion. TIME is comprised of various stromal cells, extracellular matrix (ECM), innate and adaptive immune cells, (such as, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and dendritic cells (DCs)), abnormal blood and lymphatic vessels, acidic pH, hypoxia, and high interstitial fluid pressure, that contribute to stunting antitumor immune response. [2] Moreover, immune checkpoints and negative regulatory pathways, for example, programmed cell death receptor 1 (PD1) and its ligand (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and transforming growth factor β (TGF-β) are the main culprits in TIME that promote T cell exhaustion and adaptive resistance. [3] The considerable level of interplay, complicity, and crosstalk between tumor and immune cells further adds complexity to TIME. A deeper understanding of TIME, however, is urgently needed to deal with the key mechanisms underlying the ability of TIME to evade antitumor immunity.The failure of current immunotherapeutics, such as, antibodies, immune checkpoint inhibitors, cytokines, and agonists, to target the TIME because of its complex milieu leads to tumor progression and metastasis. Preclinical and clinical studies suggest that therapeutic drugs drive cascades of systemic toxicityThe tumor immune microenvironment (TIME) is comprised of a complex milieu that contributes to stunting antitumor immune responses by restricting T cells to accumulate in the vicinity of the tumor. Nanomedicinebased strategies are being proposed as a salvage effort to reinvigorate antitumor immunity. Various strategies, however, often fail to unleash the antitumor immune response because of the paucity of appropriate therapeutic targets in the complex TIME, invigorating a fervor of investigation into mechanisms underlying the TIME to resist nanomedicines. In this review article, effective nano/biomaterial-based delivery and TIME normalization approaches that promote T cell-mediated antitumor immune response will be discussed, with a focus on emerging preclinical and clinical strategies for immune normalization. Based on currently available evidence, it seems as if the ultimate success of cancer immunotherapy and nanomedicine hinges on the capacity to normalize the TIME. Here, how nanomedicines target immunosuppressive cells and signaling pathways to broaden the impact of cancer immunotherapy are explored. Acquisition of the urgently needed knowledge of nanomedicine-mediated immune normalization will guide researchers and scientists towards clinical applications of cancer immunotherapy.

Recent advances in biomaterial-boosted adoptive cell therapy

“…Their complicated composition and physical properties, such as size, surface charge, shape, ligand density, and stiffness, can all potentially act as stimuli to unexpectedly alter the properties of the engineered immune cells. 66,194–196 Especially when used as delivery systems, biomaterials may exhibit constant biochemical or mechanical interactions with loaded immune cells, making long-term comprehensive toxicity monitoring in high demand for clinical evaluation. More importantly, the manufacture of biomaterials on a clinical scale is challenging to meet good manufacturing practice (GMP) requirements.…”

Highly expressed centromere protein L indicates adverse survival and associates with immune infiltration in hepatocellular carcinoma

“…Tumor immune microenvironment is a complex environment characterized by immunosuppression and immune escape [ 4 , 60 ]. How to restore the normal anti-tumor immune response to kill tumor cells is a research hotspot in recent years.…”

Harnessing anti‐tumor and tumor‐tropism functions of macrophages via nanotechnology for tumor immunotherapy

“…[ 5 ] More importantly, the highly dynamic TME consists of multiple biological barriers including dense extracellular matrix (ECM), high interstitial fluid pressure (IFP), heterogeneous blood supply, tumor stroma, etc., which are challenges for nanoparticles penetrating into the deep tumor site. [ 24–27 ]…”

“…[5] More importantly, the highly dynamic TME consists of multiple biological barriers including dense extracellular matrix (ECM), high interstitial fluid pressure (IFP), heterogeneous blood supply, tumor stroma, etc., which are challenges for nanoparticles penetrating into the deep tumor site. [24][25][26][27] An alternative strategy is to engineer macrophages or macrophage-derived components (including macrophage membrane and macrophage-derived extracellular vesicles (EVs)), because macrophages have natural tumorhoming capability, extravasate through the tight vascular wall, and arrive at the hypoxic area or poorly vascularized region. [21,28,29] They can also exhibit excellent stealth capability of evading the phagocytosis of mononuclear phagocyte system (MPS), leading to much long blood circulation.…”