Cotargeting TREM2 and IL2 pathways triggers multipronged anticancer immunity

Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key immunosuppressive target on tumour‐associated macrophages (TAMs), where it coordinates protumorigenic and anti‐inflammatory functions within the tumour microenvironment (TME). Unfortunately, recent clinical evidence indicates that therapeutic TREM2 blockade has suboptimal efficacy in cancer patients. Now, Von Locquenghien et al. report that MiTE‐144, a TREM2 blocking antibody fused to an IL2 variant with TME‐restricted activation, demonstrates superior anticancer efficiency compared to TREM2 blockade alone in the preclinical setting. Importantly, MiTE‐144 showed reduced systemic inflammation or hepatotoxicity relative to TREM2 blockade and/or ‘generic’ IL2 immunocytokine approaches. Detailed TME analysis of MiTE‐144‐treated tumours showed substantial reprogramming of the myeloid compartments, together with activation of NK/CD8 + T cells. While this study tackled several limitations of anti‐TREM2 monotherapy, more attention is needed towards clinically relevant immunotherapy barriers in therapy‐refractory tumour settings.