Facts and hopes of CD40 agonists as a cancer immunotherapy

Abstract CD40 agonists are a promising class of immunotherapeutic agents that potentiate both innate and adaptive immunity. This review examines the established facts and prospects of CD40 agonists in cancer immunotherapy. CD40, a co-stimulatory receptor of the TNF receptor superfamily, is found on antigen-presenting cells. CD40 activation licenses dendritic cells to prime tumor-specific T cells, polarizes macrophages to a pro-inflammatory phenotype, activates B cells, and facilitates tumor fibrosis remodeling. Preclinical models demonstrate the significant potential of CD40 agonists to induce anti-tumor immunity, leading to the development of various CD40-activating therapeutics, including monoclonal antibodies, recombinant CD40L, and ectopic expression of CD40L via gene transfer. While clinical trials show modest antitumor activity, some patients experience durable responses, especially when CD40 agonists are combined with other therapies such as immune checkpoint inhibitors and chemotherapy. These combinations, tested in traditionally difficult-to-treat cancers like pancreatic cancer, provide hope for improved outcomes. Current research focuses on refining CD40 agonist therapies through novel combination strategies, improving patient selection, and the development of tumor-targeted CD40 agonists and Fc-engineered antibodies which aim to enhance efficacy while mitigating toxicity. However, significant challenges remain, particularly in identifying patients most likely to benefit from CD40 immunotherapy and understanding resistance mechanisms. Addressing these challenges is crucial for guiding effective combination strategies and optimizing treatment outcomes. By examining both established facts and ongoing developments, this review provides a comprehensive overview of the status and potential of CD40 agonists in cancer immunotherapy.