Figure 2.

The interaction between cancer cells and stromal cells of the TME via TNFR2 signaling. TNFR2⁺ macrophages and fibroblasts are influenced by receptor binding of TNF, resulting in a transformation to tumor-associated macrophages (TAMs) and cancer-associated fibroblast (CAFs). These cells can accelerate tumor proliferation via phosphatidyl inositol 3 kinase (PI3K)/AKT activation and migration by autocrine or paracrine of chemokine C-C motif ligand 5 (CCL5)/CCR5. Malignant stromal cells are promoters of tumor burden and metastasis through angiogenesis and immunomodulation. In addition, sTNFR2 released from TAMs directly drives cancer invasion. TNFR2⁺ regulatory T cells (Tregs), which are a minor subpopulation in the normal state, accelerate proliferation and migration of malignant tissue via TNFR2 signaling and contribute to tumor growth by strongly suppressing effector T cells (Teffs). The degree of TNFR2 expression is associated with the suppressing function, expression of C-X-C motif chemokine receptor 4 (CXCR4), migration of Tregs, and predicts the prognosis of patients with malignant disease. Meanwhile, TNFR2^- Tregs, which usually express programmed cell death protein 1 (PD-1) and cytotoxic T lymphocytes-associated protein 4 (CTLA-4), are considered to play a critical role in immunomodulation in the normal state.