The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer

Abstract

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.