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Cancer Cell:魏嘉/李颜团队揭示未成熟中性粒细胞在癌症骨转移中的关键作用,并提出治疗新策略
生物世界· 2025-08-08 04:04
Core Viewpoint - The study reveals the critical role of immature neutrophils in the bone metastatic microenvironment and suggests a potential therapeutic strategy to improve cancer immunotherapy by regulating these cells [3][7]. Group 1: Research Findings - Immature neutrophils dominate the bone metastatic microenvironment in both mouse models and cancer patients [5]. - DKK1 induces neutrophils to exhibit an immature functional state, which possesses strong immunosuppressive capabilities, inhibiting CD8+ T cell anti-tumor responses [5]. - The DKK1-CKAP4-STAT6 signaling pathway drives CHI3L3 expression, essential for the immunosuppressive role of immature neutrophils in bone metastases [5]. Group 2: Therapeutic Implications - Blocking DKK1 can promote neutrophil maturation, improve the immune microenvironment, induce tumor shrinkage, and enhance responses to immune checkpoint blockade therapy [3][5]. - The findings propose a promising new strategy for combined immunotherapy targeting bone metastases by modulating neutrophil activity [7].
Immunity:衰老癌细胞释放线粒体DNA,破坏抗肿瘤免疫
生物世界· 2025-05-12 04:15
Core Viewpoint - Cellular senescence is a stable state of growth arrest closely related to age-related diseases and cancer development, characterized by an intrinsic anti-apoptotic ability and a unique secretory phenotype known as the senescence-associated secretory phenotype (SASP) [1][2]. Group 1 - Senescent tumor cells release mitochondrial DNA (mtDNA), which enhances immunosuppression mediated by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) through the cGAS-STING pathway [3][9]. - The release of mtDNA from senescent cells can exacerbate inflammation associated with tissue damage or disease progression, indicating a potential mechanism linking cellular senescence to age-related diseases and cancer [2][6]. - The study highlights that targeting the release of mtDNA could reprogram the immunosuppressive tumor microenvironment, thereby improving cancer treatment outcomes for patients undergoing chemotherapy [9][10]. Group 2 - The research team found that both naturally senescent primary cells and tumor cells undergoing senescence due to treatment actively release mtDNA into the extracellular environment [5][7]. - Extracellular mtDNA is encapsulated in extracellular vesicles and selectively transferred to PMN-MDSC, enhancing their immunosuppressive activity through the cGAS-STING-NF-κB signaling pathway [5][10]. - Pharmacological inhibition of voltage-dependent anion channels (VDAC) can reduce extracellular mtDNA levels and reverse PMN-MDSC-driven immunosuppression, improving chemotherapy efficacy in prostate cancer mouse models [6][10].