TNFSF9 (also known as 4-1BBL or CD137L) is a cytokine that functions as a costimulatory molecule through binding to its receptor TNFRSF9 (CD137/4-1BB). The protein plays a crucial role in T-cell activation and proliferation, with studies demonstrating its ability to induce proliferation of activated peripheral blood T-cells and enhance cytotoxic T cell differentiation 12. TNFSF9 operates through bidirectional signaling mechanisms, providing both forward costimulatory signals to T-cells and reverse signals that can modulate the tumor microenvironment 3. In disease contexts, TNFSF9 shows complex roles in cancer progression. It can promote tumor growth by facilitating M2 macrophage polarization through histone lactylation-dependent mechanisms in gliomas 4 and contributes to tumor-associated macrophage infiltration in Wilms' tumor via the TNFSF9-TNFRSF9 axis 5. However, therapeutic targeting of this pathway shows promise, as evidenced by tri-specific antibodies engaging TNFSF9 demonstrating enhanced antitumor efficacy through dual CD3/CD137 stimulation 2. Additionally, TNFSF9 expression is upregulated in dendritic cells under hyperglycemic conditions, contributing to diabetes-exacerbated inflammatory responses 6. The protein represents a significant therapeutic target in immunomodulation and cancer treatment strategies.