Table 3 summarizes general treatment recommendations and Table 4 summarizes some treatment recommendations regarding specific NirAEs. TABLE 3 Management of suspected neurological immune-related adverse effects (irAEs) thead valign=”top” th colspan=”2″ align=”left” rowspan=”1″ Grade/CTCAE /th th align=”center” rowspan=”1″ colspan=”1″ Management /th /thead Grade 1Mild symptomsConsider to 1alpha, 24, 25-Trihydroxy VD2 withhold ICINo interference with functionClose monitoring for any progressionSymptoms not concerning to patientIf irAEs worsen or do not improve, consider permanent discontinuationGrade 2Moderate symptomsWithhold ICICranial nerve involvement. diagnosis and early management of neuropsychiatric symptoms can be challenging. Even though pathogenesis of these complications is not fully comprehended yet, the blockade of tumoral inhibitory signals, and therefore the elicitation of cytotoxic T-cell-mediated response, seems to play a decisive role. The aim of this review was to summarize the current knowledge about the pathogenic mechanisms, clinical manifestations, and therapeutic recommendations regarding the main forms of neurotoxicity related to checkpoint inhibitors. CNS demyelination and the exacerbation of known main neurological autoimmune diseases, such as demyelinating neuropathies, myasthenia gravis, or multiple sclerosis (MS), have also been reported after exposure to ICIs. Current therapeutic recommendations for neurotoxicity related to ICIs include stop or discontinuation of immunotherapy and administration of high-dose steroids, considering the administration of intravenous immunoglobulins, plasma exchange therapy, or other immunosuppressant drugs in refractory cases. However, there is a need of further structured research to better understand and optimize the clinical management of NirAEs. A non-exhaustive systematic literature search was conducted in MEDLINE database. Several articles were obtained for the different syndromes explained in the manuscript. However, there is a lack of prospective studies to guide the correct management. Most of the data were recovered from retrospective series and single-institution experience. This is the most important limitation of our manuscript. In this review, we aimed to summarize the current available scientific data about the pathogeny, clinical phenotype, and treatment recommendations regarding the neurological toxicity of ICIs. 2 Physiopathology Due RIEG to the increasing incidence of irAEs during the last years, the 1alpha, 24, 25-Trihydroxy VD2 mechanisms involved in this type of toxicity 1alpha, 24, 25-Trihydroxy VD2 are an active research field, although many aspects regarding their pathogeny remain poorly comprehended to date. In the particular case of NirAEs, the relatively low incidence and the difficulty to obtain histological samples, especially from the CNS, have made the comprehension of the pathogenic process behind them especially challenging. The heterogeneity in clinical presentation, the various affected organs and cells, a wide spectrum on timing, and the considerable variability of the reported histological findings suggest 1alpha, 24, 25-Trihydroxy VD2 that there are different mechanisms involved, as well as some patient-specific factors that could entail an individual susceptibility to develop this kind of toxicity (Wesley et al., 2021). The current approved ICIs target PD-1, PD-L1, and CTLA-4. Monoclonal antibodies (Abs) against these molecules suppress immune inhibitory signals upon T cells, allowing T-cell proliferation, tumor acknowledgement, and destruction (Granier et al., 2017). The blockade of both CTLA-4 and PD-1/PD-L1 cell interactions has been replicated in animal models and has been found to facilitate autoimmunity (Klocke et al., 2016; Roberts et al., 2021). Although an antitumor response is the one expected, they are not tissue antigen-specific and therefore are not limited to the tumor microenvironment. As part of the immune system, you will find regulatory T cells (Tregs) that are key players in maintaining immune tolerance by actively suppressing effector T cells. Tregs also express CTLA-4 and PD-1, so they are direct targets of ICIs. This loss of immune regulation, with failure of T-cell tolerance 1alpha, 24, 25-Trihydroxy VD2 and activation of immune effector cells, may lead to the development of irAEs (Francisco et al., 2010). Tregs and other immune system cells interact and are highly regulated by cytokines. Pro-inflammatory cytokines lead to destruction, whereas anti-inflammatory cytokines help maintain immune tolerance. ICIs have shown different effects on cytokine levels, and these might be related to the pathophysiology behind irAEs. Cytokines have also been analyzed as potential prognostic biomarkers in patients treated with ICIs (Vilari?o et al., 2020). The elevated expressions of 11 pro-inflammatory cytokines (G-CSF, GM-CSF, fractalkine, FGF-2, IFNa2, IL12p70, IL1a, IL1B, IL1RA, IL2, and IL13) have been correlated with the development of severe irAEs in a cohort of melanoma patients (Lim et al., 2019). Elevated levels of interleukin 17 (IL17A) have been associated with immune-related neuroendocrine toxicity, suggesting that it can be a diagnostic and therapeutic target, although further studies are needed to validate this hypothesis (Mazzarella et al., 2020). As previously mentioned, ICIs are not cell-specific. PD-1 and CTLA-4 are expressed in numerous cells and are present in different tissue microenvironments. RNA expressions of PD-1, PD-2, and CTLA-4 were verified over the.