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P21-activated protein kinases (PAKs) are thought to be at the center of tumor signaling pathways. As a representative member of the group II PAK family, P21-activated protein kinase 4 (PAK4) plays an important role in the development of tumors, with several biological functions such as participating in oncogenic transformation, promoting cell division, resisting aging and apoptosis, regulating cytoskeleton and adhesion, as well as suppressing antitumor immune responses. PAK4 is also crucial in biological processes, including the occurrence, proliferation, survival, migration, invasion, drug resistance, and immune escape of tumor cells. It is closely related to poor prognosis and tumor-related pathological indicators, which have significant clinical and pathological significance. Therefore, this article offers a review of the structure, activation, and biological functions of PAK4 and its clinical and pathological importance. This overview should be of assistance for future research on PAK4 and tumors and provide new ideas for tumor treatment and prognostic evaluation of patients.

Background: Pyroptosis belongs to a unique type of programmed cell death among which GSDME is reported to exert anti-tumor immunity. However, the underlying mechanisms of how to boost tumor-infiltrating lymphocytes and whether it could benefit the efficacy of ICIs are still unknown. Methods: CRC samples were used to analyze its relationship with CD8+T cells. GSDME in mouse CRC cell lines CT26/MC38 was overexpressed. The infiltration of CD8+T cells in grafted tumors was determined by multiplex flow cytometric analysis and immunohistochemistry. Transcriptomic analysis was performed in cell lines to define key signatures related to its overexpression. The mechanism of how mtDNA was released by GSDME-induced mitochondrial damage and activated cGAS-STING pathway was observed. Whether GSDME benefited ICIs and the relationships with the genotypes of CRC patients were investigated. Results: It had favorable prognostic value in CRC and was positively associated with increased number and functionality of CD8+T cells both in human samples and animal models. This was due to mitochondrial damage and activation of cGAS-STING-IFNβ pathway for the recruitment of CD8+T cells. Mechanically, GSDME overexpression enhanced N-GSDME level, leading to the mitochondrial damage and mtDNA was released into cytosol. Finally, GSDME benefited with ICIs and exhibited positive relationships with MSI in CRC patients. Conclusion: We presented the mechanism of GSDME in anti-tumor immunity through activating cGAS-STING-IFNβ axis mediated by mitochondrial damage, leading to more infiltration of CD8+T cells with synergistic efficacy with ICIs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Periodontitis is a chronic inflammatory disease linked to pyroptosis, an inflammatory cell death process. Macrophages are essential for maintaining microenvironment homeostasis, which is crucial for periodontal health. This study explores the mechanisms underlying the relationship between macrophage pyroptosis and periodontitis. Methods: Expression of the pyroptosis marker gasdermin E (GSDME) and the macrophage surface marker CD68 was examined by immunofluorescence double staining in healthy and periodontitis gingival tissues. In an in vitro pyroptosis model, RAW264.7 cells were irritated using Porphyromonas gingivalis–lipopolysaccharide (P. gingivalis–LPS) after treatment with either a nuclear factor kappa‐B (NF‐κB) agonist or inhibitor. The mRNA and protein levels of NF‐κB, caspase‐3, GSDME, and interleukin‐1β (IL‐1β) were evaluated through qRT‐PCR, western blotting, and ELISA techniques. Results: GSDME and CD68 were heavily elevated in inflamed gingival tissues compared to healthy tissues and co‐localized in the same region. Furthermore, exposure to P. gingivalis–LPS resulted in a significant upregulation of NF‐κB, caspase‐3, GSDME, and IL‐1β at both the mRNA and protein levels in RAW264.7 cells. NF‐κB agonist or inhibitor pretreatment enhanced or inhibited these effects. Conclusions: GSDME‐mediated macrophage pyroptosis is implicated in periodontitis. Based on in vitro experiments, P. gingivalis‑LPS causes pyroptosis in RAW264.7 cells through the caspase‐3/GSDME pathway. Furthermore, NF‐κB regulates this pyroptotic pathway. [ABSTRACT FROM AUTHOR]