A type 2 cytokine Fc–IL-4 revitalises exhausted CD8+ T cells against cancer

Current cancer immunotherapy predominately focuses on eliciting type 1 immune responses fighting cancer; however, long-term complete remission remains uncommon. A pivotal question arises whether type 2 immunity can be orchestrated alongside type 1-centric immunotherapy to achieve enduring response against cancer. 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+ TTE) cells in the tumour. Consequently, Fc–IL-4 remarkably enhances anti-tumour efficacy of type 1 immunity-centric adoptive T cell transfer (ACT) or immune checkpoint blockade (ICB) therapies and induces durable remission across multiple syngeneic and xenograft tumour models. Mechanistically, we uncovered 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 nicotinamide adenine dinucleotide (NAD+) level of CD8+ TTE cells in a lactate dehydrogenase A (LDHA)-dependent manner. The metabolic modulation mediated by Fc–IL-4 is indispensable for reinvigorating intratumoural CD8+ TTE 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.