Pyroptosis is an inflammatory form of programmed cell death that is mediated by pore-forming proteins such as the gasdermin family (GSDMs), including GSDMA-E. Upon cleavage by activated caspases or granzyme proteases, the N-terminal of GSDMs oligomerizes in membranes to form pores, resulting in pyroptosis. Though all the gasdermin proteins have been studied in cancer, the role of pyroptosis in cancer remains mysterious, with conflicting findings. Numerous studies have shown that various stimuli, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and chemotherapeutic drugs, could trigger pyroptosis when the cells express GSDMs. However, it is not clear whether pyroptosis in cancer induced by chemotherapeutic drugs or CAR T cell therapy is beneficial or harmful for anti-tumor immunity. This review discusses the discovery of pyroptosis as well as its role in inflammatory diseases and cancer, with an emphasis on tumor immunity.

Background and Aims: HCC remains a leading cause of cancer mortality in China. Anti-angiogenic drugs (AADs) plus immune checkpoint blockade (ICB) combination therapy shows considerable promise for HCC; however, its efficacy is hampered by immunosuppression within the tumor microenvironment. High endothelial venules (HEVs) facilitate lymphocyte migration and tumor infiltration. The aim was to study the formation, functional mechanisms, and clinical relevance of HEVs in the treatment of HCC with combination therapy. Approach and Results: Single-nucleus RNA sequencing, flow cytometry, and immunohistochemistry revealed increased HEV expression and higher CD3 ⁺ T-cell infiltration in HCC tissue after a combination of AAD and ICB therapy. Multiplex immunohistochemistry and spatial analysis demonstrated that CCR7 ⁺ CD8 ⁺ T cells were spatially associated with HEVs. Pseudotime analysis of human T cells and treatment of Hepa1-6 orthotopic liver tumor mouse models with CCR7 ⁺ CD8 ⁺ T-cell transfusions were used to show that CCR7 ⁺ CD8 ⁺ T cells can differentiate into cytotoxic effector T cells. The same models demonstrated that combination therapy activated VEGFC and non-canonical NF-κB pathways, promoting HEV formation. Kaplan–Meier analysis revealed that high HEV density correlated with improved clinical response and prolonged survival. Conclusions: HEVs are pivotal in modulating immune activity within the HCC tumor microenvironment. Targeting the VEGFC–NF-κB (non-canonical)–HEV axis could be a promising therapeutic strategy to enhance antitumor immunity and improve outcomes in patients with HCC who are receiving combination AAD plus ICB therapy.

Sarcoma is a rare and heterogeneous class of mesenchymal malignancies with poor prognosis. Panobinostat (LBH589) as one of histone deacetylase (HDAC) inhibitors has demonstrated anti-tumor activity in patients with sarcoma, but its mechanisms remains unclear. Here, we found that LBH589 alone inhibited the proliferation and colony formation of soft tissue sarcoma (STS) cell lines. Transcriptome analysis showed that treatment with LBH589 augmented the NK cell-mediated cytotoxicity. Quantitative real-time PCR and flow cytometric analysis (FACS) further confirmed that LBH589 increased the expression of NKG2D ligands MICA/MICB. Mechanistically, LBH589 activated the Wnt/β-catenin pathway by upregulating the histone acetylation in β-catenin promoter. In vitro co-culture experiments and in vivo animal experiments showed that LBH589 increased the cytotoxicity of natural killer (NK) cells while Wnt/β-catenin inhibitor decreased the effects. Our findings suggest that LBH589 facilitates the anti-tumor effect of NK cells, highlights LBH589 an effective assistance drug in NK cell-based immunotherapies.

Patients diagnosed with soft tissue sarcoma (STS) often present at intermediate to advanced stages, with inherently limited therapeutic options available. There is an urgent need to identify novel therapeutic targets. In this study, by screening STS data from the Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases, KIFC1 is identified as a potential biomarker and a promising therapeutic target for STS. Notably, a significant increase in KIFC1 levels, which exhibited a strong correlation with a poor prognosis in STS patients is observed. The findings revealed that knockout of KIFC1 suppressed STS growth both in vitro and in vivo. Furthermore, KIFC1 is found to regulate cellular senescence in STS, which has not been reported before. that targeting KIFC1 induced cellular senescence via interacting with FXR1, an RNA‐binding protein is discovered, thereby further stabilizing MAD2L1 mRNA in an m6A‐dependent manner. Additionally, the suppression of KIFC1 markedly diminished the growth of patient‐derived xenografts (PDX) and triggered senescence. This study provides the first evidence that KIFC1 inhibition induces cellular senescence through MAD2L1, underscoring KIFC1 as a novel prognostic biomarker and a potential therapeutic target for STS.