TREM2⁺ tumor-associated macrophages in cancer: Context-dependent biology, biomarkers, and precision immunotherapy

Tumor-associated macrophages (TAMs) are abundant and functionally important components of the tumor microenvironment (TME), yet the molecular programs that distinguish pathogenic macrophage states from tissue-adaptive populations remain incompletely defined. Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key marker of specialized immunoregulatory macrophage states across multiple solid tumors. Accumulating evidence links TREM2⁺ macrophages to metabolic adaptation, immune evasion, and impaired antitumor immunity, although their biological functions vary substantially across tumor types, tissue niches, and disease settings. In this review, we synthesize current understanding of TREM2-associated immunobiology, including ligand recognition, signaling architecture, immunometabolic adaptation, and macrophage functional heterogeneity. We critically evaluate conflicting findings across tumor types and discuss how tissue context, macrophage ontogeny, and microenvironmental cues shape immune evasion, therapeutic responsiveness, and clinical outcomes. We further examine emerging therapeutic strategies targeting TREM2-associated myeloid programs, including antibody-based approaches, macrophage reprogramming, pathway modulation, and rational combination immunotherapy, while highlighting translational challenges, safety considerations, and biomarker-guided opportunities. Building on previous reviews of TREM2 signaling and tumor-associated myeloid biology, this review proposes a context-dependent framework integrating macrophage heterogeneity, immunometabolism, spatial biology, biomarker development, and therapeutic decision-making to advance precision immunotherapy.