As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of cancer. However, response rates even to well-established immunotherapies remain low in several types of cancer. Therefore, various novel immunomodulatory substances are currently under investigation, among them agonists of the intracellular signaling protein STING (STimulator of INterferon Genes). Activation of the STING signaling pathway can alter the cytokine profile within the tumor microenvironment (TME) and reshape the function of various immune cells. STING agonists have yielded promising results in preclinical studies, but this success has not yet been replicated in clinical trials. Consequently, STING agonists are optimized for greater potency and combined with nanotechnologies to enhance biodistribution and achieve sustained accumulation within the TME. This review summarizes a selection of STING agonists evaluated in clinical trials to date and discusses their effects on tumor-infiltration immune cells, especially macrophages. It highlights emerging candidates currently under investigation in preclinical studies, and explores nanotechnological approaches for their combinational use to enhance therapeutic efficacy.

The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.

The large T antigen (LT) of the Merkel cell polyomavirus (MCPyV) is crucial for Merkel cell carcinoma (MCC), a rare but very aggressive form of neuroendocrine skin cancer. The clonal integration of MCPyV DNA into the host genome is a signature event of this malignancy. The resulting expression of oncogenes, including the small T (sT) antigen and a truncated form of the LT (truncLT), directly contribute to carcinogenesis. The truncation of the C-terminus of LT prevents the virus from replicating due to the loss of the origin binding domain (OBD) and the helicase domain. This precludes cytopathic effects that would lead to DNA damage and ultimately cell death. At the same time, the LxCxE motif in the N-terminus is retained, allowing truncLT to bind the retinoblastoma protein (pRb), a cellular tumor suppressor. The continuously inactivated pRb promotes cell proliferation and tumor development. truncLT exerts several classical functions of an oncogene: altering the host cell cycle, suppressing innate immune responses to viral DNA, causing immune escape, and shifting metabolism in favor of cancer cells. Given its central role in MCC, the LT is a major target for therapeutic interventions with novel approaches, such as immune checkpoint inhibition, T cell-based immunotherapy, and cancer vaccines.

With the advent of immunotherapeutics, a new era in the combat against cancer has begun. Particularly promising are neo-epitope-targeted therapies as the expression of neo-antigens is tumor-specific. In turn, this allows the selective targeting and killing of cancer cells whilst healthy cells remain largely unaffected. So far, many advances have been made in the development of treatment options which are tailored to the individual neo-epitope repertoire. The next big step is the achievement of efficacious “off-the-shelf” immunotherapies. For this, shared neo-epitopes propose an optimal target. Given the tremendous potential, a thorough understanding of the underlying mechanisms which lead to the formation of neo-antigens is of fundamental importance. Here, we review the various processes which result in the formation of neo-epitopes. Broadly, the origin of neo-epitopes can be categorized into three groups: canonical, noncanonical, and viral neo-epitopes. For the canonical neo-antigens that arise in direct consequence of somatic mutations, we summarize past and recent findings. Beyond that, our main focus is put on the discussion of noncanonical and viral neo-epitopes as we believe that targeting those provides an encouraging perspective to shape the future of cancer immunotherapeutics.

Cancer remains one of the leading causes of death worldwide. New treatments like immunotherapy—especially checkpoint inhibitors and CAR-T cell therapy—have improved outcomes for some patients. However, these therapies often struggle to treat solid tumours effectively. Natural killer (NK) cells are part of the immune system and can naturally detect and destroy cancer cells without previous adaption. Scientists are now enhancing these cells by adding special receptors, called CARs (chimeric antigen receptors), to help them better recognize and attack cancer, an approach originally developed for T cells. CAR-NK cell therapy has some advantages over CAR-T therapy. It tends to cause fewer severe side effects, such as strong immune reactions or off-target effects in healthy tissues. Within some limitations, the allogenic use of CAR-NK cells is possible, as these cells exert less graft-versus-host activity. Such CAR-NK cell products can be produced in larger quantities and stored, making treatment more accessible. Still, there are challenges. It can be difficult to create enough modified NK cells, and the tumour microenvironment can block their activity. This review highlights recent progress in CAR-NK therapy, including early lab and clinical research. It also explores ways to improve these treatments and how they might work alongside other cancer therapies to help more patients in the future.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While most of the current treatment strategies focus on immune cell regulation, except for the drug siponimod, there is no therapeutic intervention that primarily aims at neuroprotection and remyelination. Recently, nimodipine showed a beneficial and remyelinating effect in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Nimodipine also positively affected astrocytes, neurons, and mature oligodendrocytes. Here we investigated the effects of nimodipine, an L-type voltage-gated calcium channel antagonist, on the expression profile of myelin genes and proteins in the oligodendrocyte precursor cell (OPC) line Oli-Neu and in primary OPCs. Our data indicate that nimodipine does not have any effect on myelin-related gene and protein expression. Furthermore, nimodipine treatment did not result in any morphological changes in these cells. However, RNA sequencing and bioinformatic analyses identified potential micro (mi)RNA that could support myelination after nimodipine treatment compared to a dimethyl sulfoxide (DMSO) control. Additionally, we treated zebrafish with nimodipine and observed a significant increase in the number of mature oligodendrocytes (* p$\le$ 0.05). Taken together, nimodipine seems to have different positive effects on OPCs and mature oligodendrocytes.