Breaking the barriers: Overcoming cancer resistance by targeting the NLRP3 inflammasome

Inflammation has a pivotal role in the initiation and progression of various cancers, contributing to crucial processes such as metastasis, angiogenesis, cell proliferation and invasion. Moreover, the release of cytokines mediated by inflammation within the tumour microenvironment (TME) has a crucial role in orchestrating these events. The activation of inflammatory caspases, facilitated by the recruitment of caspase-1, is initiated by the activation of pattern recognition receptors on the immune cell membrane. This activation results in the production of proinflammatory cytokines, including IL-1 beta and IL-18, and participates in diverse biological processes with significant implications. The NOD-Like Receptor Protein 3 (NLRP3) inflammasome holds a central role in innate immunity and regulates inflammation through releasing IL-1 beta and IL-18. Moreover, it interacts with various cellular compartments. Recently, the mechanisms underlying NLRP3 inflammasome activation have garnered considerable attention. Disruption in NLRP3 inflammasome activation has been associated with a spectrum of inflammatory diseases, encompassing diabetes, enteritis, neurodegenerative diseases, obesity and tumours. The NLRP3 impact on tumorigenesis varies across different cancer types, with contrasting roles observed. For example, colorectal cancer associated with colitis can be suppressed by NLRP3, whereas gastric and skin cancers may be promoted by its activity. This review provides comprehensive insights into the structure, biological characteristics and mechanisms of the NLRP3 inflammasome, with a specific focus on the relationship between NLRP3 and tumour-related immune responses, and TME. Furthermore, the review explores potential strategies for targeting cancers via NLRP3 inflammasome modulation. This encompasses innovative approaches, including NLRP3-based nanoparticles, gene-targeted therapy and immune checkpoint inhibitors. There are two pivotal mechanisms to surmount cancer cell resistance to immunotherapy: First, the utilization of immune checkpoint inhibitors to block PD-1 on T cells, thereby preventing its interaction with PD-L1 on tumour cells and consequently augmenting T cell-mediated anti-tumour responses. Second, targeting of the NLRP3 inflammasome within tumour cells, which serves to modulate the inflammatory milieu of the tumour microenvironment. The synergistic application of these two approaches is hypothesized to effectively overcome the resistance of cancer cells to immunotherapeutic interventions, as visually represented by the green arrow on the right side of the diagram. This innovative combinatorial strategy holds promise for enhancing the efficacy of cancer immunotherapy and potentially improving patient outcomes.image