Therapies based on PD-1 inhibitors, such as pembrolizumab and nivolumab, have shown promising results in non-small lung malignancy and melanoma but still represent a poor option in GBM due to the peculiar, large immunosuppressive state of this tumour [183,184,185,186]. in treatment response remains obscure. However, an in-depth investigation of GBMs microenvironment may lead to novel restorative opportunities to improve individuals results. This review will elucidate the GBMs microenvironment composition, highlighting the current state of the art in immunotherapy methods. We will focus on novel strategies of active and passive immunotherapies, including vaccination, gene therapy, checkpoint blockade, and adoptive T-cell therapies. (a gene coding for nuclear import of proteins); at the same time, knockdown experiments showed that glioma cell growth and invasion were significantly reduced, suggesting IL-10 like a potential target for glioma individuals treatment [162]. 5.2.4. Colony Revitalizing Element 1-CSF-1 Colony-stimulating element 1 (CSF-1) is definitely a crucial chemokine for TAMs differentiation and survival. CSF-1 works in combination with EGFR, advertising GBM cells invasion [163]. The inhibition of CSF-1 and EGFR helps prevent and reduces tumour invasion, resulting Lasmiditan in a significant improvement in individuals survival and medical end result [94,164]. 5.2.5. Cluster of Differentiation 38-CD38 CD38 is an ectoenzyme involved in TAMs Ly6a promotion and initiation, which is present on the surface of one-third of the cells [165,166]. The selective inhibition of Lasmiditan CD38 having a monoclonal FDA-approved antibody called daratumumab (DARA) enhances tumour immune recognition and reduces tumour growth in vitro and in GBM mouse models. Lasmiditan In particular, the association of TMZ and DARA generates better results in terms of anti-tumoral apoptotic effects than TMZ only [167]. In light of these data, future experiments will become necessary to understand better the part of CD38 in GBMs microenvironment [168]. 5.2.6. Programmed Death Ligand 1-PD-L1 In physiological conditions, the programmed death-1 receptor (PD-1)/Programmed death ligand 1 (PD-L1) axis takes on an active part in immune homeostasis and helps prevent autoimmune response thanks to the activation of Treg cells and the inhibition of aberrant self-reactive T-cells [169,170]. PD-L1 belongs, together with PD-L2, to the B7 proteins family. Both bind to PD-1, a receptor of the CD28/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) family [171]. The part of this axis as restorative target is well known in several solid malignancies [172,173,174]. GBM cells can upregulate the activity of the co-inhibitory pathway B7-CD28 to induce TME immunosuppression and escape from immune control [175]. In fact, PD-L1 is indicated on the surface of GBM cells, tumour infiltrating myeloid cells (TIMs), B-cells, and CNS cells. Recent data suggest that TIMs display the largest amount of PD-L1 molecules, advertised by IL-10 secreted by tumour Lasmiditan cells [176,177,178]. The binding of PD-L1 with PD-1 prospects to the activation of an immunosuppressive pathway in which the tyrosine phosphatase SHP2 dephosphorylates Zap70, downregulating the cytotoxic activity of lymphocytes and, simultaneously, enhancing Lasmiditan the migration ability of GBM cells [176]. The activity of PD-L1 is undoubtedly complex, as demonstrated by the numerous receptors to which it binds, such as PD-1, CD28, CD80 and CTLA-4. However, this mechanism grants to target multiple immune-pathway simultaneously, thanks to the inhibition of only PD-L1 [171]. Instead, PD-L2 is definitely indicated primarily by DCs rather than tumour cells, is stimulated by several TME cytokines, such as IL-15 and IL-7, and binds only to PD-1. This protein is less characterized in GBM than PD-L1, but it has been revealing like a prognostic biomarker. In particular, the overexpression of PD-L2 is related to worse overall survival in GBM individuals [171,179]. Conversely, relevant studies also showed how PD-L1 manifestation in GBMs microenvironment could have a prognostic effect; in particular, if the manifestation is high in neurons and low in GBM cells, individuals display better results [180]. In contrast, increased manifestation in glioma cells is related to high tumour grade and worse individual results [171,181]. Relating to these data, a new therapy based on the inhibition of the signalling cascade mediated by PD-1/PD-L1 has been developed to enhance GBM antigens acknowledgement from the self-immune system [182]. Preclinical studies showed a.