自然杀伤（NK）细胞是主要的先天抗肿瘤效应细胞，但其功能通常受到肿瘤微环境（TME）的限制。据报道，E3 连接酶 FBXO38 可加速肿瘤浸润 T 细胞中的 PD-1 降解，从而释放其细胞毒功能。在本研究中，我们发现癌症患者和荷瘤小鼠瘤内 NK 细胞中 FBXO38 的转录水平显着低于瘤周 NK 细胞。 NK细胞中FBXO38的条件性敲除（cKO）加速了肿瘤生长并增加了肿瘤转移。 FBXO38 缺陷导致肿瘤浸润 NK (TINK) 细胞的增殖和存活受损。从机制上讲，FBXO38缺陷增强了TGF-β信号传导，包括提高Smad2和Smad3的表达，从而抑制转录因子Eomes的表达，并进一步降低NK细胞上表面IL-15Rβ和IL-15Rγc的表达。因此，FBXO38 缺陷导致 TINK 细胞对 IL-15 反应低下。与这些观察结果一致，FBXO38 mRNA 表达与多种人类肿瘤中 TINK 细胞的增殖呈正相关。为了研究 FBXO38 的治疗潜力，用 FBXO38 过表达的人原代 NK 细胞治疗携带人类肿瘤的小鼠，结果显示肿瘤大小显着减小并延长了生存期。总之，我们的结果表明 FBXO38 维持 NK 细胞扩增和存活以促进抗肿瘤免疫，并具有潜在的治疗意义，因为它们表明 FBXO38 可用于增强基于 NK 细胞的癌症免疫治疗。

Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-β signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL-15Rβ and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity, and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell-based cancer immunotherapy.