Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

中文翻译：

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SRC激酶HCK的抑制损害小鼠STAT3依赖性胃肿瘤的生长。

在胃肿瘤上皮和免疫细胞中观察到潜在转录因子STAT3的持续激活，并与患者预后不良有关。尽管靶向激活STAT3的上游激酶可提供具有有限特异性的治疗上可行的靶标，但直接抑制STAT3仍然具有挑战性。在这里，我们提供功能性证据，证明髓样特异性造血细胞激酶（HCK）活性可以驱动STAT3依赖性上皮肿瘤在小鼠中生长，并且与基质改造和肿瘤细胞浸润以及其他巨噬细胞活化相关。因此，骨髓来源的细胞中HCK表达的遗传减少或HCK活性的系统药理抑制作用会抑制巨噬细胞的极化和上皮STAT3激活，并损害肿瘤的生长。