Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8⁺ T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.

癌症免疫疗法作为一种针对癌症的新标准治疗策略已显示出巨大的希望。然而，反应率和生存获益仍然不令人满意，因为大多数当前方法，例如使用免疫检查点抑制剂，依赖于自发的抗肿瘤免疫反应。提高免疫疗法疗效的一种可能性是积极使用佐剂或特定细胞因子促进抗肿瘤免疫。IL-33 已成为此类细胞因子疗法的候选者，但尚不清楚 IL-33 如何以及在何种情况下发挥抗肿瘤免疫作用。在这项研究中，我们使用同源小鼠模型证明了 IL-33 的有效抗肿瘤作用，其中包括显着抑制肿瘤生长和通过肿瘤浸润 CD8 ⁺上调 IFN-γ 的产生。T细胞。值得注意的是，IL-33 诱导树突细胞表达信号素 4A (Sema4A)，而 Sema4A 的缺失消除了 IL-33 的抗肿瘤活性，表明 Sema4A 是 IL-33 在小鼠中的抗肿瘤作用所必需的。总的来说，这些结果不仅表明 IL-33 和 Sema4A 作为潜在的治疗靶点，而且揭示了 Sema4A 作为树突细胞活化状态的生物标志物的潜在用途，这在癌症研究的各个领域（包括疫苗开发）中具有重要价值。