Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon^1,2. A pivotal question arises as to whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer^3,4. Here we show that an interleukin-4 fusion protein (Fc–IL-4), a typical type 2 cytokine, directly acts on CD8⁺ T cells and enriches functional terminally exhausted CD8⁺ T (CD8⁺ T_TE) cells in the tumour. Consequently, Fc–IL-4 enhances antitumour efficacy of type 1 immunity-centric adoptive T cell transfer or immune checkpoint blockade therapies and induces durable remission across several syngeneic and xenograft tumour models. Mechanistically, we discovered that Fc–IL-4 signals through both signal transducer and activator of transcription 6 (STAT6) and mammalian target of rapamycin (mTOR) pathways, augmenting the glycolytic metabolism and the nicotinamide adenine dinucleotide (NAD) concentration of CD8⁺ T_TE cells in a lactate dehydrogenase A-dependent manner. The metabolic modulation mediated by Fc–IL-4 is indispensable for reinvigorating intratumoural CD8⁺ T_TE cells. These findings underscore Fc–IL-4 as a potent type 2 cytokine-based immunotherapy that synergizes effectively with type 1 immunity to elicit long-lasting responses against cancer. Our study not only sheds light on the synergy between these two types of immune responses, but also unveils an innovative strategy for advancing next-generation cancer immunotherapy by integrating type 2 immune factors.

目前的癌症免疫疗法主要集中在引发对抗癌症的 1 型免疫反应;然而，长期完全缓解仍然不常见^1,2。出现了一个关键问题，即 2 型免疫是否可以与 1 型为中心的免疫疗法一起协调，以实现对癌症的持久反应^3,4。在这里，我们表明白细胞介素 4 融合蛋白 （Fc-IL-4） 是一种典型的 2 型细胞因子，直接作用于 CD8⁺ T 细胞并富集肿瘤中功能性终末耗竭的 CD8⁺ T （CD8⁺ T_TE） 细胞。因此，Fc-IL-4 增强了 1 型免疫为中心的过继性 T 细胞转移或免疫检查点阻断疗法的抗肿瘤疗效，并在几种同基因和异种移植肿瘤模型中诱导持久缓解。从机制上讲，我们发现 Fc-IL-4 通过信号转导和转录激活因子 6 （STAT6） 和哺乳动物雷帕霉素靶标 （mTOR） 途径发出信号，以乳酸脱氢酶 A 依赖性方式增强糖酵解代谢和 CD8⁺ T_TE 细胞的烟酰胺腺嘌呤二核苷酸 （NAD） 浓度。由 Fc-IL-4 介导的代谢调节对于振兴瘤内 CD8⁺ T_TE 细胞是必不可少的。这些发现强调 Fc-IL-4 是一种有效的基于 2 型细胞因子的免疫疗法，可与 1 型免疫有效协同，从而引发针对癌症的持久反应。我们的研究不仅阐明了这两种类型的免疫反应之间的协同作用，还揭示了一种通过整合 2 型免疫因子来推进下一代癌症免疫治疗的创新策略。