Application of nanomaterials in antitumor immune response enhancement

Cancer cells are well recognized by immunotolerance characteristics, which include low immunogenicity, weak antigen presentation, low T cell infiltration, and high expression of inhibitory receptors and cytokines. This typical mechanism allows cancer cells to easily avoid the attack by immune cells, resulting in immune escape. Due to unique properties, such as adjustable size, unique surface properties, and ease of modification, nanomaterials have shown great potential in the field of immunotherapy. In this review, we summarize several ways in which nanomaterials can enhance the immune response against tumor cells. Therefore, we presently discuss the potential mechanisms involved in the induction of immune response by a series of nanomaterials. As a result, we also propose the generation of more advanced and tumordriven nanomaterials, as well as their potential applications in tumor immunotherapy. According to the route of tumor immunity, we have currently classified nanomaterials into three categories: (1) Nanomaterials with inherent immunoregulatory functions, (2) nanomaterials that, upon an exogenous response, trigger immunogenic cell death and/or enhance immune responses, and (3) nanomaterials that are used as delivery vehicles to unload other immune-activating molecules (e.g., chemical drugs, photosensitizers, proteins and DNA plasmids) to tumors or immune cells as well as immune-activating molecules that may enhance an immune response. Some natural or synthetic nanomaterials can inherently stimulate macrophage polarization and enhance immune response. As such, nanomaterials may polarize M2 macrophages into M1 macrophages by regulating the cellular phenotype, reversing the tumor immune microenvironment and, ultimately, improving an immune cell killing activity. Cytokines or compounds with immune stimulating functions can enhance an immune response by promoting the proliferation of immune cells such as T lymphocytes and NK cells. Moreover, some nanomaterials rely on their own electrical properties or responsiveness to the tumor microenvironment, leading to tumor cell immunogenic death and/or enhancing anti-tumor immune responses. Nanomaterials have been widely used in photothermal, magnetocaloric and radiation therapies as well as into other fields, due to their unique optical, electrical, and magnetic properties. Recently, it has been discovered that some of these properties may "switch" tumor cells from non-immunogenic to immunogenic cells (i.e., immunogenic cell death) and, consequently, enhance an anti-tumor immune response. Compared with an endogenous response that mostly relies on characteristics of the tumor microenvironment, rationally designed nanomaterials that are responsive to exogenous responses can more effectively enhance the immune response at the tumor site and then achieve a more precise and tractable treatment. Hence, here we introduce the notion of an enhanced immune response, dependent on the use of nanomaterials co-stimulated by exogenous responses such as near-infrared light response, magnetic field response and others. Lastly, some substances, such as drugs, photosensitizers, proteins, plasmids, are unable to elicit a robust immune response when used without a carrier. In addition, some agents can also cause tissue damage and/or local toxicity when solely used for treatment. Thus, these substances often need to be combined with nanomaterials to achieve high biological loads, targeted delivery, controllable release and other functions to safely and efficiently enhance the anti-tumor immune response. Nevertheless, current research on nanomaterial-based immunotherapy is still under development, and the translation for clinical application is still challenging. Therefore, advances in the development of innovative therapeutic nanomaterials will offer great potential for improving the effectiveness of immunotherapy.