Molecular medicine (Cambridge, Mass.) · 2026
HEATR1 deficiency enhanced gastric cancer cell PANoptosis to boost anti-tumor immunity.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Huang Ya, Xu Qingcheng, Zhu Meijuan, Shen Yawei, Zhang Xianwen
Аннотация
BACKGROUND: Despite the promise of immune checkpoint inhibitors (ICIs) for gastric cancer (GC) treatment, limited cytotoxic T cell infiltration remains a major barrier to therapeutic efficacy. This study investigates whether targeting HEAT repeat containing 1 (HEATR1) can induce immunogenic PANoptosis to enhance anti-tumor immunity.
METHODS: Bioinformatics analysis of TCGA-STAD cohort, syngeneic mouse models, and patient-derived organoids (PDOs) were employed to assess HEATR1 function. Mechanistic studies examined STAT1/IRF1 signaling, PANoptosis markers, and dendritic cell (DC) activation. Therapeutic efficacy was evaluated in combination with anti-PD1 immunotherapy.
RESULTS: HEATR1 expression inversely correlated with CD8+ T cell infiltration in GC tissues and was associated with advanced tumor stage and lymph node metastasis. HEATR1 knockdown suppressed tumor growth in immunocompetent but not T cell-deficient mice, demonstrating immune-dependency. Mechanistically, HEATR1 deficiency stabilized STAT1 by inhibiting proteasome-mediated degradation, thereby sensitizing GC cells to IFN-γ-induced PANoptosis through STAT1/IRF1 signaling activation. This inflammatory cell death released damage-associated molecular patterns, which promoted DC maturation and cross-priming of CD8+ T cells. The resulting IFN-γ secretion established a positive feedback loop amplifying tumor cell PANoptosis. PDO models confirmed that HEATR1-silenced organoids exhibited enhanced PANoptosis and DC-mediated CD8+ T cell expansion. HEATR1 knockdown synergized with anti-PD1 therapy to significantly inhibit tumor progression.
CONCLUSIONS: HEATR1 deficiency enhances GC cell sensitivity to IFN-γ-mediated PANoptosis via STAT1/IRF1 pathway activation, creating an immunogenic tumor microenvironment that potentiates ICI efficacy. These findings identify HEATR1 as a promising therapeutic target for improving GC immunotherapy outcomes.
METHODS: Bioinformatics analysis of TCGA-STAD cohort, syngeneic mouse models, and patient-derived organoids (PDOs) were employed to assess HEATR1 function. Mechanistic studies examined STAT1/IRF1 signaling, PANoptosis markers, and dendritic cell (DC) activation. Therapeutic efficacy was evaluated in combination with anti-PD1 immunotherapy.
RESULTS: HEATR1 expression inversely correlated with CD8+ T cell infiltration in GC tissues and was associated with advanced tumor stage and lymph node metastasis. HEATR1 knockdown suppressed tumor growth in immunocompetent but not T cell-deficient mice, demonstrating immune-dependency. Mechanistically, HEATR1 deficiency stabilized STAT1 by inhibiting proteasome-mediated degradation, thereby sensitizing GC cells to IFN-γ-induced PANoptosis through STAT1/IRF1 signaling activation. This inflammatory cell death released damage-associated molecular patterns, which promoted DC maturation and cross-priming of CD8+ T cells. The resulting IFN-γ secretion established a positive feedback loop amplifying tumor cell PANoptosis. PDO models confirmed that HEATR1-silenced organoids exhibited enhanced PANoptosis and DC-mediated CD8+ T cell expansion. HEATR1 knockdown synergized with anti-PD1 therapy to significantly inhibit tumor progression.
CONCLUSIONS: HEATR1 deficiency enhances GC cell sensitivity to IFN-γ-mediated PANoptosis via STAT1/IRF1 pathway activation, creating an immunogenic tumor microenvironment that potentiates ICI efficacy. These findings identify HEATR1 as a promising therapeutic target for improving GC immunotherapy outcomes.