Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3 ) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated fibroblasts comprise the R-spondin 3–producing cells, NK cells and T cells correspondingly express the R-spondin 3 receptor LGR6 within the tumor microenvironment (TME). Exogenous expression or intratumor injection of R-spondin 3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+ T cells independently and cooperatively contributed to R-spondin 3–induced control of distinct tumor types. The effect of R-spondin 3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin 3 expression enhanced tumor sensitivity to anti–PD-1 therapy, thereby highlighting new therapeutic avenues. Significance: Our study identifies novel targets in enhancing antitumor immunity and sensitizing immune checkpoint inhibition, which provides a rationale for developing new immunotherapies against cancers. It also offers mechanistic insights on Wnt signaling–mediated modulation of anticancer immunity in the TME and implications for a putative R-spondin–LGR6 axis in regulating NK-cell biology. This article is highlighted in the In This Issue feature, [p. 2945][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译：

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肿瘤微环境衍生的 R-spondins 增强抗肿瘤免疫力以抑制肿瘤生长并提高免疫检查点阻断治疗的敏感性

自然杀伤 (NK) 细胞和 T 细胞是抗肿瘤免疫反应的关键效应物和检查点抑制剂的主要靶点。在多种癌症类型中，我们发现 Wnt 信号增强剂 R-spondin 基因（例如 RSPO3 ）的表达与良好的预后相关，并且与 NK 细胞和 T 细胞的基因特征呈正相关。尽管内皮细胞和癌症相关成纤维细胞包括产生 R-spondin 3 的细胞，但 NK 细胞和 T 细胞在肿瘤微环境 (TME) 内相应地表达 R-spondin 3 受体 LGR6。R-spondin 3 在肿瘤中的外源表达或瘤内注射增强了细胞毒性效应细胞的浸润和功能，从而导致肿瘤消退。NK 细胞和 CD8+ T 细胞独立且协同地促进了 R-spondin 3 诱导的对不同肿瘤类型的控制。R-spondin 3 的作用部分是通过上调 MYC 和核糖体生物发生来介导的。重要的是，R-spondin 3 表达增强了肿瘤对抗 PD-1 治疗的敏感性，从而突出了新的治疗途径。意义：我们的研究确定了增强抗肿瘤免疫力和提高免疫检查点抑制敏感性的新靶点，这为开发新的抗癌免疫疗法提供了依据。它还提供了关于 Wnt 信号介导的 TME 中抗癌免疫调节的机制见解，以及推定的 R-spondin-LGR6 轴在调节 NK 细胞生物学中的意义。本文在 In This Issue 功能中突出显示，[p. 2945][1][1]：