not-yet-known not-yet-known not-yet-known unknown 3.5 CD40 (TNF Receptor Superfamily Member 5) CD40, also referred to as TNF receptor superfamily member 5 (TNFRSF5), is an essential co-stimulatory receptor predominantly found on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells. It is also expressed on non-immune cells such as endothelial, epithelial, and mesenchymal cells (including fibroblasts, myofibroblasts, synoviocytes, stellate cells, etc.), as well as on platelets and tumor cells [328]. CD40 was initially identified as a surface marker on bladder carcinoma cells and B cells [329]. When CD40 interacts with its ligand, CD40 ligand (CD40L or CD154), which is primarily expressed on activated T cells, a cascade of signaling events is initiated. This interaction leads to the activation and maturation of APCs, enhancing their ability to present antigens and provide co-stimulatory signals to T cells [330]. CD40 engagement also promotes the secretion of pro-inflammatory cytokines such as interleukin-12 (IL-12), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) from APCs, which are crucial for promoting T cell activation and differentiation into effector cells [331]. Agonistic antibodies that specifically activate CD40 have been developed and investigated in preclinical and clinical studies [332]. Preclinical studies have demonstrated that CD40 agonists can induce potent anti-tumor immune responses, including increased infiltration of cytotoxic T cells into tumors, enhanced tumor cell killing, and tumor regression. Furthermore, CD40 activation can lead to the generation of long-lasting memory T cells, providing durable protection against tumor recurrence [332, 333]. Several phase 1 clinical trials have evaluated CD40 agonists like recombinant CD40L [334], CP-870,893 (Fully human IgG2 mAb) [333] , SGN-40 (Humanized IgG1 mAb) [335],  initial findings from these studies show objective clinical responses and immune modulation in the absence of significant toxicity [333]. In a phase I clinical trial of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma, monoclonal antibody was well tolerated with encouraging preliminary response data [336].