CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily of receptors expressed on a variety of cell types. The CD40–CD40L interaction gives rise to many immune events, including the licensing of dendritic cells to activate CD8+ effector T cells, as well as the facilitation of B cell activation, proliferation, and differentiation. In malignant cells, the expression of CD40 varies among cancer types, mediating cellular proliferation, apoptosis, survival and the secretion of cytokines and chemokines. Agonistic human anti-CD40 antibodies are emerging as an option for cancer treatment, and early-phase clinical trials explored its monotherapy or combination with radiotherapy, chemotherapy, immune checkpoint blockade, and other immunomodulatory approaches. In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them. [Display omitted] • CD40L-CD40 signaling plays an intricate role in regulation of immune and malignant cells in the tumor microenvironment. • CD40 is linked to both biological and immunological functions. • Preclinical studies and clinical development of CD40 agonism therapies underscore its significance in cancer treatment. • Careful management of dosage optimization and adverse effects is crucial for future design of CD40 agonism cancer therapy. • Cytokine therapies, RAS/RAF/PI3K pathway targeted therapies, and CART therapies can potentially be incorporated with CD40 agonism therapy. [ABSTRACT FROM AUTHOR]