Macrophage-targeted immunocytokine leverages myeloid, T, and NK cell synergy for cancer immunotherapy.

Abstract

Tumor-associated macrophages (TAMs) expressing the myeloid checkpoint TREM2 are key immunosuppressive cells in the tumor microenvironment (TME), driving tumor progression and contributing to poor prognosis in cancer patients. Due to their pivotal role, TAMs have emerged as a promising target for immunotherapies. However, current TAM-targeting monotherapies show limited efficacy, highlighting the need for strategies engaging multiple immune modalities. Here, we developed myeloid-targeted immunocytokines and natural killer (NK)/T cell enhancers (MiTEs) harnessing myeloid and lymphoid synergy for immunotherapy. MiTEs are trans-acting immunocytokines with tumor-specific activation, allowing dual targeting of TAMs and lymphocytes by TREM2 antagonism and cytotoxic effector cell activation through interleukin (IL)-2. To avoid off-target toxicities, MiTEs contain an IL-2 masking moiety, which is cleaved by a TAM-specific protease. MiTEs demonstrate high efficacy in preclinical tumor models through extensive immune reprogramming spanning TAM, T, and NK cell compartments. MiTEs show transformative potential for treating solid cancers by inducing potent multi-axis anti-tumor immunity while minimizing toxicities.