Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.

Apoptosis associated speck like protein containing CARD (ASC) is widely researched and recognized as an adaptor protein participating in inflammasome assembly and pyroptosis. It contains a bipartite structure comprising of a pyrin and a caspase recruitment domain (CARD) domain. These two domains help ASC function as an adaptor molecule. ASC is encoded by the gene PYCARD. ASC plays pivotal role in various diseases as well as different homeostatic processes. ASC plays a regulatory role in different cancers showing differential regulation with respect to tissue and stage of disease. Besides cancer, ASC also plays a central role in sensing, regulation, and/or disease progression in bacterial infections, viral infections and in varied inflammatory diseases. ASC is expressed in different types of immune and non-immune cells. Its localization pattern also varies with different kinds of stimuli encountered by cell. This review will summarize the literature on the structure cellular and tissue expression, localization and disease association of ASC.

Nucleotide binding domain, leucine-rich repeat containing proteins (NLRs) are a family of pattern recognition receptors involved in major innate immune defense mechanisms. NLRs play a key role in several cancers, autoimmune, and inflammation-associated diseases. Association of NLRP3 has been widely investigated in neurodegenerative diseases, chronic alcoholism, depression, traumatic brain injury, and pathogenic infections. Several research studies have shown possible involvement of various other inflammasome-forming and non-inflammasome-forming NLRs in the brain; however, their mechanisms of action are yet to be defined clearly. Our review provides a comprehensive overview of the expression of NLRs in human brain and their critical association with inflammation and neurodegenerative diseases. The review also summarizes promising NLR-targeted therapeutics and their prospects for brain pathologies.

NLRs (nucleotide-binding domain, leucine-rich repeat containing receptors) are pattern recognition receptors associated with immunity and inflammation in response to endogenous and exogenous pathogen and damage associated molecular patterns (PAMPs and DAMPs respectively). Dysregulated NLR function is associated with several diseases including cancers, metabolic diseases, autoimmune disorders and autoinflammatory syndromes. In the last decade, distinct cell and organ specific roles for NLRs have been identified however; their roles in cancer initiation, development and progression remain controversial. This review summarizes the emerging role of NLRs in cancer and their possible future as targets for cancer therapeutics.