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.