A tumor-associated macrophage-targeted immunocytokine leveraging T and NK cell synergy for potent cancer immunotherapy [CITE-seq]

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 a new class of cancer immunotherapies: myeloid-targeted immunocytokines and NK-T cell enhancers (MiTEs). 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 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-arm anti-tumor immunity and minimizing toxicities.