Several immunoregulatory or immune checkpoint receptors including T cell immunoglobulin and mucin domain 3 (TIM-3) have been implicated in glioblastoma progression. Rigorous investigation over the last decade has elucidated TIM-3 as a key player in inhibiting immune cell activation and several key associated molecules have been identified both upstream and downstream that mediate immune cell dysfunction mechanistically. However, despite several reviews being published on other immune checkpoint molecules such as PD-1 and CTLA-4 in the glioblastoma setting, no such extensive review exists that specifically focuses on the role of TIM-3 in glioblastoma progression and immunosuppression. Here, we critically summarize the current literature regarding TIM-3 expression as a prognostic marker for glioblastoma, its expression profile on immune cells in glioblastoma patients and the exploration of anti-TIM-3 agents in glioblastoma pre-clinical models for potential clinical application.

Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4⁺ and CD8⁺ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4⁺ and CD8⁺ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4⁺ and CD8⁺ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4⁺ and CD8⁺ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.

Glioblastoma is the most aggressive form of brain tumor resulting in low overall patient survival rates of 12–15 months post diagnosis. Several factors contribute to the complexity of the tumor, including tumor heterogeneity, blood–brain barrier complications, genetic defects, cancer stem cell generation, and immune evasion. These factors can result in the progression of glioblastoma and are controlled by signaling pathways. Some of the signaling pathways involved in glioblastoma progression include ERK, NF-κB, Wnt, and PI3K/AKT/mTOR. Our and others’ previous studies have found that TIM-3 and TGF-β signaling is altered in glioblastoma patients and may contribute to cancer progression. Immune promoting pathways such as STING have also been studied in glioblastoma to enhance anti-tumor immunity; however the interconnecting roles of these pathways are not well described. This review highlights the role of these three key cancer-related pathways in glioblastoma and their mechanistic link. Better understanding these links may result in improved treatment targets or disease progression biomarkers.

Glioblastoma is the most aggressive primary brain malignancy, characterised by extensive intra-tumoural heterogeneity, therapy resistance, and a profoundly immunosuppressive tumour microenvironment. The galectin family, a group of β-galactoside-binding lectins, has emerged as a key regulator of tumour biology, influencing oncogenesis, immune modulation, and therapy resistance. In this study, we performed an integrative bioinformatics analysis to systematically evaluate the expression patterns, prognostic significance, genetic alterations, and functional roles of galectin family members in glioblastoma. We utilised publicly available genomic datasets and computational tools to perform our analysis, including UALCAN, GEPIA, cBioPortal, STRING, GeneMANIA, DAVID, and TIMER. We identified LGALS1, LGALS3, and LGALS9 as significantly upregulated in glioblastoma, with their overexpression correlating with adverse patient survival. Functional enrichment analysis highlighted galectin-mediated pathways involved in extracellular matrix remodelling, immune dysregulation, tumour-promoting pathways, and protein processing, suggesting their pivotal role in glioblastoma pathogenesis. We also show that transcriptional and immunological signatures suggest that galectins may regulate glioblastoma immunosuppression, extracellular matrix remodelling, and protein homeostasis. Our findings provide novel insights into the oncogenic and immunoregulatory roles of galectins in glioblastoma, establishing their potential as prognostic biomarkers and therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer with low five-year overall survival rates of ~10% from diagnosis. The immune ‘cold’ tumor microenvironment (TME) of PDAC is a key contributor to tumor progression, featuring immunosuppression in conjunction with a reactive stroma. The immune composition of the TME is highly tumor-promoting, with the presence of immunosuppressive cells and the absence of effector and cytotoxic immune cells. Further to this, the active stroma region of the tumors contains transformed fibroblasts which communicate with tumor and immune cells to further enhance immunosuppression. Fundamental cellular processes such as T cell exhaustion, metabolic signaling, epigenetic modifications, and a series of genetic mutations can all contribute to PDAC progression and poor patient outcomes. This review describes the key mechanisms behind immune dysregulation in PDAC, highlighting the importance of this area and the essential research that is necessary.

Pregnancy associated plasma protein-A (PAPP-A) plays an integral role in breast cancer (BC), especially triple negative breast cancer (TNBC). This subtype accounts for the most aggressive BC, possesses high tumor heterogeneity, is least responsive to standard treatments and has the poorest clinical outcomes. There is a critical need to address the lack of effective targeted therapeutic options available. PAPP-A is a protein that is highly elevated during pregnancy. Frequently, higher PAPP-A expression is detected in tumors than in healthy tissues. The increase in expression coincides with increased rates of aggressive cancers. In BC, PAPP-A has been demonstrated to play a role in tumor initiation, progression, metastasis including epithelial-mesenchymal transition (EMT), as well as acting as a biomarker for predicting patient outcomes. In this review, we present the role of PAPP-A, with specific focus on TNBC. The structure and function of PAPP-A, belonging to the pappalysin subfamily, and its proteolytic activity are assessed. We highlight the link of BC and PAPP-A with respect to the IGFBP/IGF axis, EMT, the window of susceptibility and the impact of pregnancy. Importantly, the relevance of PAPP-A as a TNBC clinical marker is reviewed and its influence on immune-related pathways are explored. The relationship and mechanisms involving PAPP-A reveal the potential for more treatment options that can lead to successful immunotherapeutic targets and the ability to assist with better predicting clinical outcomes in TNBC.