Programmed cell death in cancer: targeting necroptosis to kill tumor cell
Cell Death Discovery, Published online: 06 April 2026; doi:10.1038/s41420-026-03002-4
Programmed cell death in cancer: targeting necroptosis to kill tumor cellCell Death Discovery, Published online: 06 April 2026; doi:10.1038/s41420-026-03002-4
Programmed cell death in cancer: targeting necroptosis to kill tumor cellTransl Oncol. 2026 Apr 3;67:102748. doi: 10.1016/j.tranon.2026.102748. Online ahead of print.
ABSTRACT
BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtype-specific risk loci, a critical gap remains in understanding how plasma proteins influence immune-cell traits and contribute to EOC pathogenesis.
METHODS: We integrated subtype-stratified GWAS data from two EOC cohorts with plasma proteomics and immune-cell traits to construct protein-immune-EOC regulatory landscapes using a three-stage Mendelian randomization framework. Single-cell RNA-seq and multiplex immunofluorescence were employed to delineate the cellular distribution and spatial context of causal proteins. Subsequent analyses characterized immune infiltration, macrophage polarization, and clinicopathological associations. Drug-gene correlations were used to identify potential therapeutic targets, and transcriptomic analyses were applied to delineate the underlying transcriptional landscape.
RESULTS: We identified 20 subtype-specific protein-immune-EOC regulatory axes, with FCGR2B emerging as a causal plasma protein in immune regulation and high-grade serous ovarian cancer (HGSOC) progression. FCGR2B was highly expressed in tumor-associated macrophages and was associated with an M2-like polarization phenotype. Functional characterization revealed that FCGR2B was associated with shorter progression-free survival and an immunosuppressive tumor microenvironment. Transcriptomic analyses revealed altered NF-κB signaling upon FCGR2B knockdown, and drug-response data suggested a potential association between high FCGR2B expression and sensitivity to NF-κB inhibitors.
CONCLUSIONS: These findings delineate subtype-specific genetically informed protein-immune regulatory landscapes in EOC and identify FCGR2B as a key immunoregulatory and prognostic biomarker in HGSOC, suggesting FCGR2B as a potential therapeutic vulnerability that warrants further investigation.
PMID:41934917 | DOI:10.1016/j.tranon.2026.102748
JHEP Rep. 2026 Mar 23:101824. doi: 10.1016/j.jhepr.2026.101824. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally. Radiofrequency ablation (RFA) is a widely used treatment for HCC, but its efficacy is often limited by tumor relapse. Neutrophils, serve as a double-edged sword in tumor immunology, have recently been implicated in anti-tumor immunity post-RFA. Shear wave elastography (SWE) is a non-invasive examination for liver tissue, and associated with immune response. This study investigates the correlation between dynamic change of SWE values and neutrophils response following RFA, and explores potential adjuvant strategies for RFA.
METHODS: We conducted a comprehensive analysis using both clinical data from patients undergoing RFA (n=102) and experimental studies in mouse models (n=4-6 per group). Single-cell RNA sequencing (scRNA-seq) and multi-omics analyses including multiplex immunofluorescence staining and flow cytometric analysis were performed to identify neutrophil subsets. To assess the therapeutic potential of neutrophils-activating therapy for enhancing anti-tumor immunity post-RFA, we tested CD40 agonist in combination with RFA in preclinical models.
RESULTS: We noticed that rising liver SWE values following RFA were significantly associated with reduce relapse (n=102, p<0.001), and demonstrated that this phenomenon was linked to the inflammatory environment induced by the infiltration of neutrophils (2.5-fold increase, p<0.001). scRNA-seq analysis identified neutrophil subsets characterized by high expression of interferon-stimulated genes, which exhibited potent anti-tumor activity via nitric oxide. Importantly, treatment with CD40 agonist significantly augmented this immune response, leading to reduced tumor growth in mice (149.6±38.12 mm3 vs 23.92±4.43 mm3, p=0.008).
CONCLUSIONS: We linked clinical features to neutrophil-mediated immunity post-RFA. Neutrophil-activating therapy like CD40 agonists may prevent HCC relapse after RFA.
PMID:41881314 | DOI:10.1016/j.jhepr.2026.101824
Cell Death Discovery, Published online: 07 March 2026; doi:10.1038/s41420-026-02953-y
TRIM27-controlled endothelium-derived exosomes play a central role in podocyte injury in diabetic kidney disease