Antibody targeting of the TNF-TNFR2 axis to overcome tumor immune resistance.

Tumor necrosis factor (TNF) exerts paradoxical effects in cancer, driven by the differential engagement of its two receptors, TNFR1 and TNFR2. While TNFR1 mediates cytotoxic signaling, accumulating evidence indicates that TNFR2 predominantly orchestrates tumor-promoting inflammation and immunosuppression within the tumor microenvironment (TME). TNFR2 is highly expressed on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and malignant cells, forming a coordinated network that drives immune evasion and contributes to resistance to immune checkpoint blockade (ICB). In this review, we dissect the structural and functional distinctions between transmembrane and soluble TNF and discuss how these differences shape receptor-specific signaling outcomes. We further highlight emerging therapeutic strategies targeting the TNF-TNFR2 axis, including monoclonal antibodies, antibody-drug conjugates (ADCs), and bispecific antibodies, with an emphasis on their ability to selectively remodel the immunosuppressive TME. Finally, we discuss key challenges for clinical translation, including on-target toxicity, patient stratification, and context-dependent TNFR2 biology, and outline future directions such as biomarker-guided therapy and tumor-restricted targeting approaches. Together, these advances position TNFR2 as a promising therapeutic node for overcoming resistance to current immunotherapies.