cells Review Nano-Enhanced Cancer Immunotherapy: Immunology Encounters Nanotechnology Ernesto Bockamp 1,2 , Sebastian Rosigkeit 1,2 , Dominik Siegl 1,2 and Detlef Schuppan 1,2,3, * 1 Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; bockamp@uni-mainz.de (E.B.); srosigke@uni-mainz.de (S.R.); dosiegl@students.uni-mainz.de (D.S.) 2 Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany 3 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA * Correspondence: detlef.schuppan@unimedizin-mainz.de; Tel.: +49-6131-17-7356 Received: 17 August 2020; Accepted: 11 September 2020; Published: 15 September 2020   Abstract: Cancer immunotherapy utilizes the immune system to fight cancer and has already moved from the laboratory to clinical application. However, and despite excellent therapeutic outcomes in some hematological and solid cancers, the regular clinical use of cancer immunotherapies reveals major limitations. These include the lack of effective immune therapy options for some cancer types, unresponsiveness to treatment by many patients, evolving therapy resistance, the inaccessible and immunosuppressive nature of the tumor microenvironment (TME), and the risk of potentially life-threatening immune toxicities. Given the potential of nanotechnology to deliver, enhance, and fine-tune cancer immunotherapeutic agents, the combination of cancer immunotherapy with nanotechnology can overcome some of these limitations. In this review, we summarize innovative reports and novel strategies that successfully combine nanotechnology and cancer immunotherapy. We also provide insight into how nanoparticular combination therapies can be used to improve therapy responsiveness, to reduce unwanted toxicity, and to overcome adverse effects of the TME. Keywords: immune checkpoint inhibitor; CAR T cell therapy; bi-specific antibody therapy; tumor microenvironment; macrophage; myeloid derived suppressor cells (MDSC); PD-1; PD-L1; siRNA; toll like receptor (TLR) 1. Introduction Cancer immunotherapy can provide powerful and long-lasting anti-cancer responses in patients with advanced or metastasized tumors that are otherwise resistant to conventional therapy [1]. Mechanistically and illustrated by the clinical efficacy of immune checkpoint inhibitors (ICIs), cancer immune therapies aim to increase the overall fitness of the immune system by interfering with key immune regulatory mechanisms [2]. As exemplified by chimeric antigen receptor (CAR) T cell therapies, a second powerful mode of action for immunotherapies is to redirect the destructive power of adaptive immune cells towards patient-specific tumor targets [3]. Despite the undisputed clinical efficacy and long-term response rates of immunotherapies observed in various cancer types, the majority of patients receiving treatment will not benefit from immunotherapy and some initially responding patients will eventually relapse [4,5]. In addition and owing to the enhanced immune responses and potential severe off-target effects, significant immune toxicities have been observed in patients receiving therapies with ICIs and CAR T cells [6]. Extensive preclinical research and first clinical data demonstrate that nanotechnology can overcome some of the challenges that currently limit cancer immunotherapy (Figure 1). Cells 2020, 9, 2102; doi:10.3390/cells9092102 www.mdpi.com/journal/cells