Tumor-targeted IL-10 combined with IL-2 amplifies anti-tumor immunity

Tumor-targeting cytokines have emerged as a promising strategy for cancer immunotherapy, although their mechanisms of action often remain complex. In this study, we developed a novel approach by combining tumor-targeted IL-10 (CmAb-(IL10)2) with IL-2 (CmAb-IL2) to enhance antitumor immunity while minimizing Immune-Related Adverse Events (irAEs). We demonstrated that endogenous IL-10 plays a critical role in IL-2-mediated antitumor effects, and importantly, the combination of CmAb-(IL10)2 and CmAb-IL2 preferentially expands less-exhausted CD8+ T cells within tumors. Mechanistically, we identified that the IL-10/IL-10 receptor (IL-10R) axis in dendritic cells (DCs) is critical for mediating the efficacy of this combination therapy by promoting intratumoral DC function. Our findings reveal that tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity through the IL-10/IL-10R/DC axis within tumors, while mitigating IL-2-associated irAEs through the IL-10/IL-10R/macrophage axis. This approach offers a promising IL-10 based strategy to improve the efficacy of immunotherapy while reducing irAEs.